Treatment of hepatitis C in HIV-infected persons: A work in progress☆
Article Outline
As the era of effective antiretroviral therapy (ART) enters its second decade, liver disease due to hepatitis C virus (HCV) infection has emerged as a leading cause of morbidity and mortality [1]. Further, randomized controlled trials have established the relative safety and efficacy of combination therapy with peginterferon alfa (PegIFN) and ribavirin (RBV) for the treatment of hepatitis C in HIV-infected patients [2], [3], [4], [5], [6]. Based on these data, United States and European regulatory authorities have approved the use of PegIFN/RBV combination therapy in coinfected patients; similarly, multiple expert guidelines have been published to establish the standard of care in the management of HCV/HIV coinfected patients [7], [8], [9], [10], [11].
In early 2005, experts in hepatology and infectious diseases met to develop a consensus of opinion on the treatment of HCV in HIV-infected persons (First European Consensus Conference, ECC, Paris, France, March 2005) [7]. In addition to universal screening of all HIV-infected persons for hepatitis C, the ECC jury recommended that treatment with peginterferon alfa (alfa-2a, 180
mcg/weekly or alfa-2b, 1.5mcg/kg/weekly) and ribavirin (HCV genotype 1 or 4: weight-based 1000–1200mg/day; HCV genotype 2 or 3: 800mg/day) be considered in every patient in whom the benefits of therapy outweigh the risks. Persons with a high likelihood of treatment benefit (sustained virologic response, SVR) are those with: HCV genotype 2 or 3 infection; HCV genotype 1 and low HCV RNA level (<800,000IU/mL); absence of cirrhosis; younger age (<40 years) and higher CD4 cell count (>200/mm3). Importantly, the panel indicated that persons with drug addiction and psychiatric disease should be considered for HCV treatment on a case-by-case basis. These recommendations have been largely endorsed by similar expert panels convened by the United States (US) National Institute of Health, the American Association for the Study of Liver Disease/Infectious Diseases Society of America, the US Public Health Service and the Veterans Affairs Administration [7], [8], [9], [10], [11]. Thus, experts in the US and Europe have reached consensus on how best to address the growing problem of HCV-related liver disease in HIV-infected patients. Nonetheless, many clinicians recognize that the implementation of these recommendations in the “real world” has been challenging.
In some settings, few HIV-infected patients have been referred for management of hepatitis C and even fewer have undergone treatment. For example, ∼7% of 6502 coinfected US veterans have been prescribed HCV treatment and were significantly less likely to be treated compared to those with HCV alone [12]. Similarly, in the Swiss HIV cohort, 160 of 2150 (7.4%) HCV seropositive persons received HCV treatment [13]. In the urban, Johns Hopkins HIV clinic, only one-third of 845 coinfected patients were referred by their primary HIV clinicians for HCV management. Of those who were fully evaluated, only 45% were medically eligible to receive HCV treatment. In this study, active injection drug use (IDU, 54%) and untreated HIV infection (42%) were commonly reported in coinfected persons not referred for HCV care [14]. Indeed, because HCV infection is frequently acquired through IDU, active substance abuse, mental illness, and untreated HIV infection are more common in persons with HIV/HCV coinfection compared to those with HIV alone. Thus, these “real world” reports of limited HCV treatment effectiveness reflect the relatively high prevalence of medical and psychiatric comorbid conditions in coinfected persons, which are often related to active substance abuse.
While these and other observations present a relatively bleak picture of our efforts to manage hepatitis C in HIV-infected persons, it is important to recognize that these data represent the experience observed before the regulatory approval of PegIFN/RBV for coinfection and the publication of consensus HCV treatment guidelines (i.e., Swiss cohort, 1/2001–10/2004; Johns Hopkins cohort, 1998–2003). So, at this juncture it is appropriate to ask: has the management of HCV infection improved following these important events? The study by Cacoub and colleagues [15] in this issue of the Journal suggests that the answer to this question is a qualified “yes.” In this study, the researchers surveyed physicians involved in HIV treatment in urban areas of France to assess changes in care of HCV in HIV-infected persons between November 2004 (pre-ECC) and April 2006 (post-ECC). While the study sampling technique has several major limitations (e.g., only patients who attended a clinic visit during a single 1-week interval were surveyed), the findings suggest that French physicians trained in infectious diseases, internal medicine and hepatology are implementing current guidelines for the management of HCV disease.
First, 63% of the coinfected patients included in the 2006 survey had been appropriately evaluated for HCV disease with both viral (HCV RNA level and genotype) and liver damage (biopsy or non-invasive) assessments compared to only 47% in the 2004 survey. Interestingly, while liver biopsy was performed in 54–56% of patients at both time points, the use of non-invasive techniques to assess HCV-related liver disease stage was much more common in the 2006 survey with ∼44% of patients undergoing serum biomarkers and/or transient elastography, representing a major shift in clinical practice. Since accurate knowledge of liver disease stage is a critical component to the assessment of the potential risks and benefits of PegIFN/RBV therapy in an individual patient, these observations suggest that the use of non-invasive disease staging modalities may help to overcome the barrier of liver biopsy to the management of HCV infection. Indeed, in the 2006 survey, physicians indicated that access to liver biopsy was a reason for non-treatment in only 18% of patients (compared to 33% in 2004). Second, the proportion of coinfected patients who had never received HCV treatment (after removing those whose treatment status was unknown ∼6% in both surveys) decreased significantly from 58% to 42% in the 2004 and 2006 surveys, respectively. Importantly, the observed increase in the rate of HCV treatment was consistent across physician and patient groups, including patients with a history of injection drug use and those infected with HCV genotype 1. While the survey data on sustained viral response in this study are incomplete, the researchers suggest the rate of HCV eradication in these coinfected patients treated in the community was ∼30% at both time points, indicating that more patients were likely to have benefited in the later survey since many more received HCV treatment.
While overall these data suggest that French physicians have made important strides in the delivery of HCV care, the results of the 2006 physician survey suggest that significant barriers to HCV treatment in HIV-infected persons remain. In the 2006 survey, physicians reported that contraindications to treatment (e.g., mental illness) and/or concerns regarding potential adherence to therapy (e.g., active drug use) remained relatively common. Similarly, in the Johns Hopkins HIV clinic, Mehta and colleagues found that the failure of HIV care providers to refer coinfected persons for HCV management was strongly associated with active illicit drug use (injection or non-injection) and advanced or untreated HIV disease (CD4 cell count <200/mm3 and/or HIV RNA >400copies/mL) [14]. Interestingly, in this cohort, the receipt of psychiatric care was associated with an increased likelihood of HCV referral, suggesting that mental illness represents a modifiable barrier to HCV care. Furthermore, in the Johns Hopkins HIV clinic, the proportion of coinfected persons increased over time from <1% in 1998 to 28% in 2003, suggesting similar trends in improved access to HCV care are also evident in the United States. Taken together, these and other studies suggest that while progress has been made in the management of HCV infection in HIV-infected persons, substantial barriers to HCV eradication remain. While some barriers are not modifiable (e.g., poor response in patients with genotype 1/high HCV RNA), many challenges to successful HCV treatment may be overcome with aggressive medical interventions, such as those to treat advanced HIV disease, active drug/alcohol use, and unstable psychiatric disease. As suggested by Cacoub and colleagues, the management of these complicated medical and social comorbidities common among persons with coinfection requires a multi-disciplinary approach including experts in HIV disease, liver disease, substance abuse and psychiatry as well as trained nurses and pharmacists.
Thus, in the second decade of effective ART, the standard approach to HCV infection in HIV-infected persons is increasingly clear: HIV-infected persons must be screened for HCV infection using sensitive immunoassays. To confirm the presence of chronic infection, all HCV seropositive persons should be tested for HCV RNA using a qualitative or quantitative assay. Chronically infected patients must be further evaluated by experts in the treatment of HCV infection to determine eligibility for therapy with PegIFN/RBV. Persons who are not currently eligible to receive HCV treatment should be referred for management of comorbid conditions and re-evaluated at regular intervals to determine if these barriers have been overcome (e.g., successful treatment of depression). Coinfected patients who are determined to be eligible for HCV treatment ought to undergo HCV genotype testing and liver disease staging (liver biopsy, serum markers and/or elastography). Following complete evaluation, physicians must carefully weigh the potential benefits and risks of therapy for each individual, taking into account that the best predictor of treatment response may be the HCV RNA level after 4 weeks of PegIFN/RBV (i.e., following a therapeutic trial). Coinfected persons treated with PegIFN/RBV should be followed closely to permit aggressive management of adverse effects and to assess early virologic response at treatment weeks 4 and 12. Recently, Payan and colleagues reported that the failure to suppress HCV RNA level to less than 460,000IU/mL after 4 weeks of therapy was 100% predictive of virologic failure in coinfected persons enrolled in the ANRS HC02-RIBAVIC Study [16]. Coinfected persons with insufficient HCV RNA response at treatment weeks 4 and/or 12 should stop therapy whereas those responding should complete 48 weeks of therapy. Of course, even with the appropriate delivery of this standard of care, far too many coinfected patients are simply not candidates for current HCV therapies and, in those who are treatment candidates, rates of treatment and SVR remain relatively low. Thus, while clinical practice is improving, the management of HCV infection in HIV-infected persons continues to be a work in progress.
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☆ Dr. Sulkowski declares that he receives research grants or funding/lecture sponsorships/honoraria for continuing medical education (CME) programs from, or advisor or consultant for Boehringer Ingelheim, Human Genome Sciences, Bristol-Myers-Squibb, Novartis, Vertex, Merck, Roche, and Schering, and government grants or research funding R01 DA-11602, DA-16065, and DA-13806. NIH funded study.
PII: S0168-8278(07)00583-1
doi:10.1016/j.jhep.2007.10.006
© 2007 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.