World J Gastroenterol. 2011 August 7; 17(29): 3369-3374.
Published online 2011 August 7. doi: 10.3748/wjg.v17.i29.3369.
Copyright©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
Neuropsychological alterations in hepatitis C infection: The role of inflammation
Marco Senzolo, Sami Schiff, Cristina Maria D’Aloiso, Chiara Crivellin, Evangelos Cholongitas, Patrizia Burra and Sara Montagnese. Marco Senzolo, Cristina Maria D’Aloiso ,Chiara Crivellin, Patrizia Burra, Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University Hospital of Padua, 35128 Padua, Italy Sami Schiff, Sara Montagnese, Department of Clinical and Experimental Medicine, University Hospital of Padua, 35128 Padua, Italy Evangelos Cholongitas, The Royal Free Sheila Sherlock Liver Centre and Department of Surgery, UCL and Royal Free Hospital, Pond Street, London NW3 2QG, United Kindom
Author contributions: Senzolo M and Montagnese S designed of the study and wrote the manuscript; Schiff S, Cholongitas E and Crivellin C reviewed the literature; D’Aloiso CM and Burra P performed the study on cytokines in hepatitis C virus.
Correspondence to: Dr. Marco Senzolo, Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University Hospital of Padua, Via Giustiniani 2, 35136, Padua, Italy. marcosenzolo@hotmail.com
Telephone: +39-49-8218726 Fax: +39-49-8760820
Abstract
About 50% of patients with hepatitis C virus (HCV) infection complain of neuropsychiatric symptoms, “brain fog”, weakness, fatigue, and exhibit some degree of quality of life impairment, irrespective of the severity of liver disease. Since the first observation of HCV-related cognitive deficits, 10 studies have been published that have evaluated neuropsychiatric performance in patients with HCV infection and different degrees of hepatic impairment. Unfortunately, these have often included patients with cirrhosis, patients who had acquired the infection through previous intravenous drug misuse, who had a history of relatively recent treatment with interferon, or were on psychoactive medication. In addition, different neuropsychological batteries and tests that explored different cognitive domains were used, which makes the results of the studies difficult to compare. Finally, limited information is available on the pathogenesis of HCV-related cognitive impairment. Cerebral and/or systemic inflammation may be important players but their potential role has not been substantiated by experimental data. The present review outlines the available evidence of the presence of cognitive impairment in patients with HCV infection, with a focus on the potential relationship with cerebral and/or systemic inflammation.
Keywords: Cognitive alterations, Hepatitis C virus, Inflammation
INTRODUCTION
Hepatitis C virus (HCV) infection affects up to 2% of the world population and almost 4 million people in America. Although evolution to chronic HCV infection is extremely common, only 30% of chronically infected patients go on to develop end-stage liver disease and hepatocellular carcinoma.
The occurrence of hepatic encephalopathy is well documented in patients with viral cirrhosis, as in patients with cirrhosis of other etiologies[1]. However, in recent years, there has been growing evidence that alterations in cerebral function in patients with chronic HCV infection may appear long before the development of severe liver fibrosis/cirrhosis. These alterations cannot be ascribed to hepatic encephalopathy. About 50% of patients with HCV infection complain of neuropsychiatric symptoms, “brain fog”, weakness, fatigue, and exhibit some degree of quality of life impairment, irrespective of the severity of liver disease[2]. These alterations do not seem to relate to HCV genotype or replication[3]. Their etiology is unclear but it has been hypothesized that it is related to: (1) a direct effect of HCV on the brain; or (2) the neurotoxic effect of HCV-related systemic inflammation.
In the present review, we outline the available evidence of cognitive impairment in patients with HCV infection, and the possible role of cerebral and systemic inflammation
COGNITIVE ALTERATIONS IN PATIENTS WITH HCV LIVER DISEASE
Early in the course of infection, patients with HCV infection report symptoms like fatigue, malaise, weakness and problems in maintaining attention and recalling information. These alterations can interfere with their ability to perform their activities, thus leading to impairment in health-related quality of life, which is well documented[4-12]. In addition, although treatment of chronic HCV infection can temporarily worsen health-related quality of life, the relationship between sustained viral response and improvement in quality of life is also well accepted[13].
The first significant evidence for a specific role of HCV in causing cerebral function abnormalities was produced in 2001 by Forton and colleagues, who detected cerebral metabolic abnormalities (elevated choline/creatine ratio) in the frontal white matter and basal ganglia of HCV-infected patients, using proton magnetic resonance spectroscopy (1H MRS); these alterations were not present in either controls or patients with HBV infection[14]. In the following year, the same group showed significant impairment in concentration and working memory in 27 HCV-infected patients with active viral replication, compared to 20 controls and 16 anti-HCV-positive but HCV-RNA-negative patients[15].
Since these original observations, 10 studies have been published that have evaluated neuropsychiatric performance in patients with HCV infection and different degrees of hepatic impairment. Unfortunately, these have often included patients with cirrhosis (potentially, also those with minimal hepatic encephalopathy); patients who had acquired the infection by previous intravenous drug misuse; patients who had a history of relatively recent treatment with interferon; patients on psychoactive medication; or those who complained of significant fatigue; all of which could impinge on cognitive performance, in terms of motivation and psychomotor speed. In addition, different neuropsychological batteries and tests that explore different cognitive domains have been utilized, which makes it difficult to compare the results of the studies.
Hilsabeck and colleagues have documented a prevalence of cognitive dysfunction which ranged from 0% on a design copy task to 49% on a measure of sustained attention in a group of 66 HCV-infected patients; 44 (66%) of whom had cirrhosis[16]. The HCV-infected patients were compared to a cohort of 14 patients with liver disease of other etiology, who had normal cognitive performance. However, within the study group, there were factors that could have contributed to cognitive impairment, such as previous alcohol intake and HIV co-infection; the control group also included patients with previous alcohol misuse and those with cirrhosis, and possibly minimal hepatic encephalopathy. The authors were able to correlate the degree of fibrosis with that of cognitive impairment, and suggested that the latter might parallel progressive liver injury in HCV-infected patients. However, the inclusion of even a small number of patients with cirrhosis and hepatic encephalopathy might well be responsible for the correlations observed. In addition, sustained attention, which was found to be abnormal in almost half of the study group, is known to be impaired in patients with hepatic encephalopathy[17,18].
When the same authors administered a similar test battery to an independent group of HCV-infected patients, 33% of whom had cirrhosis, there was no correlation between perceived cognitive impairment, fatigue or depression and neuropsychological performance, which suggests that the latter might not be clinically relevant[19]. Similarly to the previous study, a correlation was observed between neuropsychological performance and the degree of fibrosis, which led the authors to suggest that progressive liver injury might result in worsening neuropsychiatric function in HCV-infected patients. Within this setting, it would be difficult to explain how a significant proportion of patients with HCV-related cirrhosis, just like those with cirrhosis of other etiology, would show completely normal neuropsychiatric function on extensive screening for hepatic encephalopathy.
The issue of the relationship between cognitive impairment and perceived fatigue in HCV-infected patients was subsequently addressed by Weissenborn and colleagues, who compared neuropsychological performance in 30 PCR-positive HCV-infected patients with normal liver function, 15 of whom reported moderate to severe fatigue[20]; patients with previous drug misuse, interferon treatment, psychiatric disease and patients on psychoactive drugs were excluded. The authors found a significant deficit in attention and higher executive function in patients compared to controls, in parallel with an increase in depression and anxiety. Patients with self-reported fatigue performed worse on the neuropsychological battery, whereas there was no correlation between anxiety/depression and cognitive performance. In the same study, patients with HCV infection showed a significant decrease of the N-acetyl-aspartate/creatine ratio in the cerebral cortex on 1H MRS, while the electroencephalogram was slowed in 25%[20]. In contrast, in a published abstract, Montagnese and colleagues have reported on an unexpectedly high prevalence of fast (β-dominated) electroencephalograms in a similarly well-selected population of HCV-infected patients. Similar features had been previously reported in HIV-infected individuals[21] and could be related to some degree of desynchronization of the cerebral electrical activity.
McAndrews and co-workers have confirmed the presence of minor attention deficits and impairment in verbal learning ability in their study of 37 well-selected HCV patients without disease-associated risk factors, such as substance misuse, cirrhosis or depression[22]. When compared with 46 age-matched controls, 13% of patients with HCV infection showed impairment in verbal learning ability; however, the chosen threshold for a pathological performance was 1.5 SDs below the norm, which is stricter than the usual 2 SDs. The authors themselves qualify the detected abnormalities as having limited clinical relevance. As in previous studies, McAndrews and colleagues also detected an increase in choline and a reduction in N-acetyl aspartate by MRS in the central white matter of patients compared to controls.
In contrast, Fontana and co-workers have found that 33% of 177 patients with HCV infection and advanced fibrosis who were enrolled in the HALT-C trial could be considered to have cognitive impairment (before interferon and ribavirin treatment), based on a composite score of 10 neuropsychological tests[23]. The most affected domains were verbal recall and working memory. However, 38% of patients had cirrhosis, and working memory is known to be impaired in patients with cirrhosis and hepatic encephalopathy[24], which was probably a significant confounder in this study. In addition, 50% of patients had been alcohol misusers and 46% had a history of intravenous drug abuse. In contrast with the findings by Hilsabeck and colleagues, Fontana and co-workers observed no relationship between cognitive alterations and the degree of fibrosis or mood disturbances[23].
More recently, Lowry and colleagues studied neuropsychiatric function in a well-selected, homogeneous cohort of 20 female, iatrogenically-infected patients; of whom, 11 were positive for HCV RNA and nine had spontaneously cleared the virus[25]. The authors showed that PCR-positive women had significantly poorer scores in the areas of memory, auditory recognition and sustained attention compared to a small group of nine healthy controls; these abnormalities were not present in the PCR-negative women.
To date, two studies that explored cognitive function in chronically HCV-infected patients were completely negative. The first was published by Cordoba and colleagues[26], who showed normal neuropsychiatric performance in 40 HCV patients with normal hepatic function; however, these individuals still exhibited some degree of quality of life impairment. In the same study, significant alterations in attention, executive function and motor performance were detected in a control group of patients with HCV-related cirrhosis. In contrast to most previous studies, Cordoba and co-workers selected their HCV-positive patients amongst healthy individuals screened for blood donation[26]; this is a fairly different population compared to patients with known chronic HCV infection.
The second negative study included 103 HCV-PCR-positive young patients (aged 6-19 years) who were studied with the Adaptive Behavioural and WAIS scales. In this group, the time lag between infection and cognitive assessment might have been significantly lower compared to the other, adult cohorts, thus possibly explaining, at least to some extent, the negative results[27].
One study that compared cognitive performance in 32 patients with chronic hepatitis C against 29 chronic hepatitis B showed than HCV patients had worse performance in verbal learning and memory compared to controls, but they did not differ from patients with hepatitis B virus liver disease[28]. However, about 20% of patients had liver cirrhosis in both groups. Moreover, only 50% of the study group had histological assessment and no clinical exclusion of cirrhosis was described by the authors.
INFLAMMATION AND HCV
The etiology of cognitive dysfunction in patients with chronic HCV infection remains unclear but two hypotheses have been put forward: (1) the virus infects the brain and has a direct neurotoxic effect; and (2) the virus is indirectly neurotoxic via cerebral and/or systemic inflammation.
A direct neurotoxic role for HCV is supported by reports of HCV replication within the central nervous system[29-31]. It has been suggested that the virus enters the brain by infecting peripheral blood mononuclear cells, which are precursors of the microglia and could act as a “Trojan horse”[32]. However, data on the association between the virus in the brain and impaired cognitive function are still lacking. Indeed, replication of quasispecies is very low within the brain; HCV RNA is almost undetectable in the cerebrospinal fluid[33,34] and there is no correlation between viral load and cognitive impairment in patients with HCV infection[20]. However, this is sometimes also the case for other HCV-related complications, such as cryoglobulinemia or vasculitis[35].
It is well known that the cytolytic effect of HCV within the liver relates to the activation of the immune system. Thus, chronic activation of the immune system could account, at least in part, for the observed cerebral alterations, due to increased systemic and/or local inflammation. A growing body of evidence supports immune system-to-brain communication, with peripheral immune activation being associated with behavioral, affective and cognitive disturbances. Peripheral proinflammatory cytokines such as interleukin (IL)-1, and IL-6 are likely mediators of these effects, and penetrate the blood-brain barrier directly through active transport mechanisms, activation of the vagus nerve, stimulation of neurotransmitter systems, and therefore, modulation of brain activity. Most of the evidence that directly links peripheral proinflammatory cytokines with neurocognitive function is derived from animal models, in which increased peripheral IL-1 and IL-6 are associated with increased levels of these cytokines in the prefrontal cortex and hippocampus[36].
Increased levels of IL-6 have been associated with impairment in spatial learning and memory, which are prevented by the administration of specific antagonists. This suggests a primary role for inflammatory cytokines in mediating cognitive decline and deficits in chronic inflammation[37,38]. Likewise, peripheral markers of inflammation have been associated with cognitive decline in elderly patients. In a recent study that evaluated the correlation between IL-6 and cognitive performance in middle-aged volunteers, an inverse relationship was observed between circulating levels of IL-6 and auditory recognition memory, attention, working memory and executive function[39].
Once a patient has chronic HCV infection, proinflammatory cytokines such as IL-6, IL-4 and tumor necrosis factor (TNF)-α are produced and may be elevated for several decades. During this period, proinflammatory cytokines can cross the blood-brain barrier and therefore contribute to cognitive impairment.
Moreover, another possible contribution of inflammation to cognitive degeneration in HCV patients is local cerebral inflammation[34,40,41]. It has been shown that small amounts of HCV within the brain evoke a local inflammatory response, because macrophages infected with HCV in vitro can induce TNF-α and IL-8[32]. In addition, a recent study has shown activation of brain macrophages/microglia in autopsy brain tissue from HCV-positive patients[42]. Peripheral markers of the activation of cellular immunity have recently been assessed by Gess and colleagues in a group of 53 HCV-infected patients with mild liver disease. No association was observed between activated cellular immunity and subjectively perceived or objectively measured cognitive impairment[43].
FUTURE PERSPECTIVES
The studies that have explored cognitive function in patients with chronic HCV were extremely heterogeneous in terms of patient characteristics, confounding factors (e.g. intravenous drug misuse and previous alcohol intake), control groups, methodology and tests used to assess cognitive performance. An additional issue might be the fact that the study subjects ranged from patients who had cleared HCV to those with HCV-related cirrhosis, even within the same study group. Furthermore, the role of systemic inflammation in the pathogenesis of cognitive alterations in patients with HCV infection has never been directly explored.
It is possible that patients with chronic HCV infection and persistently normal transaminases for 6 mo (PNALT) could represent an extremely useful study group to provide additional information, particularly in relation to the role of HCV per se in causing neurocognitive dysfunction. When we evaluated systemic inflammation in this group of patients, no activation of systemic inflammation was observed[44]. This finding suggests that patients with normal transaminases have a different immunological response profile, compared to those whose transaminases remain elevated. In line with this hypothesis, previous studies have demonstrated an increase in HCV-specific CD4+CD25+ regulatory T cells and a decrease in CD4+ response in patients with normal transaminases compared to patients with high transaminases[45].
Whether the absence of an activated systemic inflammatory response in PNALT patients also reflects better cognitive performance needs to be explored. In a preliminary study, we found that PNALT patients with normal serum levels of proinflammatory cytokines performed similarly to controls as far as memory, attention and cognitive evoked potential N400, which relates to semantic memory and verbal working memory. Patients with chronic hepatitis due to HCV had impairment in memory in 60% of cases, with concomitant increased amplitude of N400, which indicated the need for increased neuronal recruitment to perform the task[44].
In the two studies that did not demonstrate cognitive alterations in patients with HCV, HCV-positive individuals were selected from healthy volunteers screened for blood donation and young patients with hemophilia, respectively. These subjects were classified as HCV-positive individuals with normal transaminases but were not further characterized, and some might well have qualified as PNALT.
Future, prospective cohort studies should probably include patients with chronic HCV infection with minimal or no fibrosis, PNALT, hepatitis B surface antigen-positive patients with/without transaminitis and a control group with chronic systemic inflammation (i.e. inflammatory bowel disease). In addition, the neuropsychological evaluation should probably be conducted in a structured, comprehensive way, by cognitive domain, and test results scored against adequate, large and local normative databases, rather than simply compared to small internal control groups. Mood, fatigue and quality of life should also be assessed. This approach might provide more solid information on whether HCV-related cognitive impairment exists and, if so, on its clinical relevance.
Footnotes
Peer reviewers: Yukihiro Shimizu, MD, PhD, Kyoto Katsura Hospital, 17 Yamada-Hirao, Nishikyo, Kyoto 615-8256, Japan; Alexandra A Alexopoulou, MD, 2nd Department of Internal Medicine, University of Athens, Medical School, Hippokration General Hosp, 40 Konstantinoupoleos St, 16342 Hilioupolois Athens, Greece
S- Editor Tian L L- Editor Kerr C E- Editor Zheng XM
References
Sunday, September 4, 2011
Watch-HIV/HCV-What Matters Most
A Colorado resident describes living with hepatitis C in one of a series of videos created in a joint project of the Colorado Department of Public Health and Environment, the University of Colorado-Denver and Denver's Center for Digital Storytelling. Marty Otañez, principal investigator and assistant professor of anthropology, led the video project. For more information, visit www.hepatititscolorado.info .
Saturday, September 3, 2011
Telaprevir-Incivek/Boceprevir-Victrelis-Paying For Hepatitis C Treatment
Vertex, Merck face little payer pushback with newly marketed HCV drugs
By Christine Livoti
Published: September 2 2011 16:35
Last updated: September 2 2011 16:35
This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. http://www.biopharminsight.com/
--------------------------------------------------------
Vertex Pharmaceuticals’ (NASDAQ: VRTX) Incivek (telaprevir) and Merck’s (NYSE: MRK)
Victrelis (boceprevir) are largely being reimbursed by payers, after a prior authorization period of one to four weeks, hepatologists told Biopharm Insight. In some instances, there has been payer pushback with telaprevir due to its higher price, some experts noted.
Both drugs were approved in May, as a treatment for hepatitis C (HCV) in combination with pegylated-interferon and ribavirin.
Telaprevir is currently priced at USD 49,200 for 12 weeks of therapy, while boceprevir is priced at USD 1,100 per week, for a total treatment cost of anywhere between USD 26,400 to USD 48,400 depending on individual patient response to therapy.
Mitchell Davis, DO, medical director at the Hepatitis Treatment Institute of Florida, said there was some outcry from the community on the pricing of these new agents, but both manufacturers have established “aggressive” patient assistance programs.
Vertex’s co-pay assistance covers up to 20% of the total cost of telaprevir for people who pay out-of-pocket or have an insurance co-pay, regardless of household income. If the co-pay is less than the 20% of the prescription price, the drug will be free.
The Vertex Free Medicine Program will provide telaprevir at no cost to people who do not have insurance, are not covered by other benefits programs, and have an annual household income of USD 100,000 or less, according to a company press release.
Merck is offering a discount co-pay card that will allow eligible individuals to save up to USD 200 on up to 12 boceprevir prescriptions for up to 48 weeks, though many people will not need to be treated that long, according to a company press release.
Ultimately, patients don’t care about the total cost, but what their co-pay is, said Dr Paul Pockros, head of the Division of Gastroenterology and Hepatology, Scripps Clinic. Pockros, who has written an estimated 60 prescriptions starting patients on triple therapy, said payers have been reasonable. Dr Melissa Palmer, director of Hepatology at NYU Hepatology Associates, estimated writing nearly 250 prescriptions in total for both drugs, and added she has faced no issues so far with reimbursement.
Dr Doris Strader, associate professor of medicine, Division of Gastroenterology, University of Vermont College of Medicine, estimated a prior authorization period of three to four weeks. Generally, it is slightly longer than the prior authorization period with pegylated-interferon and ribavirin, she noted.
There is a “pretty quick turnaround” from payers with regards to these two new HCV drugs, said Dr Michael Epstein, gastroenterologist and founder of Digestive Disorders Associates in Annapolis, Maryland. He noted that his center often works through specialty benefits pharmacies to take “a lot of the sting” out of the process. Dr Tarek Hassanein, a hepatologist and medical director at Southern California Liver Centers, similarly reported using specialty benefits pharmacies to make the process easier.
A Merck spokesperson said specialty pharmacies have a legacy position in HCV in offering pegylated-interferon and ribavirin, and it is expected they will continue to maintain an important role, with Merck having a long-term strategy to work with that channel.
Payer requirements
Having written 20-30 prescriptions for triple therapy, Hassanein said thus far, only two of his patients have been denied coverage. Those payers did not provide clear reasons for denying coverage, he noted. Davis added he has heard from the community that some payers have chosen to cover one drug but not the other -- although it has not happened in his practice.
Pockros noted he has particularly been having difficulty with Blue Cross of California, which is the biggest payer by volume for his practice. This specific insurance company has been requiring a USD 19,000 co-pay for telaprevir. The Vertex patient assistance program covers roughly USD 10,000, and the remaining difference is still too large of a financial burden to patients. This is in stark contrast to some other payers, which require only a USD 50 monthly co-pay.
“We are putting some of these patients on boceprevir, because it costs less,” Pockros said.
The Merck spokesperson said Victrelis has received a preferred or exclusive position in the formularies of some public payers, based first on its safety and efficacy proposition, followed by its dollar value proposition.
Dr Michael DeMicco, a gastroenterologist with Associated Gastroenterology Medical Group in Anaheim, California, said he has encountered some difficulty with other payers based in California, including Medi-Cal and CalOptima.
Multiple letters detailing how sick the patient is have to be sent, along with their likelihood of developing cirrhosis, a common complication in HCV patients, to get the new drugs approved by these payers, DeMicco explained. These payers have been “very resistant,” he added. However, Dr Sammy Saab, associate clinical professor of medicine, Division of Digestive Diseases and the Division of Liver and Pancreas Transplantation at UCLA, said the specialty pharmacies his center works through have noted that Medi-Cal has been the easiest payer to work with.
Payers have been asking for a baseline viral load and checking the genetic basis of a patient’s disease, said Pockros, as both drugs are currently approved for use only in only some HCV patients, who are classified as Genotype 1. Coverage was denied for off-label use in a Genotype 2 patient, he noted.
Epstein said for each patient, he typically provides payers with a clinical evaluation that was conducted within the last month, the patient’s lab results from the last 90 days and a liver biopsy test from within the past year.
Payers largely have not been asking for any interim treatment data, such as week four HCV RNA viral load, which indicates a patient’s response to treatment, several sources noted, though some mentioned having heard this occurring elsewhere. Ethically, “I don’t know how [payers] can wait for that viral load,” said Palmer, as the time lag could result in a patient missing doses while waiting for additional authorization.
Once prior authorization is received, payers have been deferring to clinician judgment on whether to continue therapy or not, said Strader. For telaprevir, with a total duration of treatment of only 12 weeks, some interim lab results might only be returned after the patient completes treatment, she said. With boceprevir, maybe some interim lab data would be returned while still during the course of treatment.
Praise for HCV patient assistance programs
Both companies have been generous about patient support, said Pockros, particularly for patients that fall in the Medicare Part D “donut hole.” Though his center rarely sees Medicare patients, Davis noted that it is difficult for these patients, as they are unable to pre-pay to gain access to these new drugs, unless they have a secondary pharmaceutical plan.
The prior authorization period can take longer when patients have additional financial concerns, Davis added. Some additional financial paperwork has to be done, which is usually a disclosure the patient makes under a income cap, he said. The companies have not been asking for tax returns in these cases, he added.
Pockros discussed a telaprevir patient who had insurance, but then lost his job two weeks into treatment. By the time the patient notified Pockros, he had only three days to get the patient telaprevir so he would not miss a dose, but the patient’s COBRA insurance still had not gone into effect. Pockros said he was able to contact Vertex, and the company was able to ship the drug to the patient, in order to avoid missing any doses.
Palmer reported a scenario for a boceprevir patient, where the specialty pharmacy did not get the drug to the patient in time, but found that Merck was unable to get drug to the patient in this scenario. She said she brought this situation to Merck directly, and that the company is actively working to get a program in place.
The Merck spokesperson said scenarios like these do happen, which are outside of the company’s control, and the usual process by which a patient receives his/her drug. He said Merck has put into place both supply chain and specialty pharmacy initiatives to try to ensure rapid, immediate, and uninterrupted drug supply, but that “there are always going to be those wrinkles” to the usual process.
Both Pockros and Palmer said they typically keep pegylated-interferon and ribavirin on hand for such scenarios, but that there are currently no samples available for either drug, with physicians left to rely on these gap programs instead.
Vertex could not be reached for comment.
Read More:
http://www.ft.com/intl/cms/s/2/d1970424-d575-11e0-bd7e-00144feab49a,dwp_uuid=e8477cc4-c820-11db-b0dc-000b5df10621.html#axzz1WteuehVo
Patient Assistance Program
INCIVEK/Telaprevir and VICTRELIS (Boceprevir) Patient Assistance Programs
By Christine Livoti
Published: September 2 2011 16:35
Last updated: September 2 2011 16:35
This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. http://www.biopharminsight.com/
--------------------------------------------------------
Vertex Pharmaceuticals’ (NASDAQ: VRTX) Incivek (telaprevir) and Merck’s (NYSE: MRK)
Victrelis (boceprevir) are largely being reimbursed by payers, after a prior authorization period of one to four weeks, hepatologists told Biopharm Insight. In some instances, there has been payer pushback with telaprevir due to its higher price, some experts noted.
Both drugs were approved in May, as a treatment for hepatitis C (HCV) in combination with pegylated-interferon and ribavirin.
Telaprevir is currently priced at USD 49,200 for 12 weeks of therapy, while boceprevir is priced at USD 1,100 per week, for a total treatment cost of anywhere between USD 26,400 to USD 48,400 depending on individual patient response to therapy.
Mitchell Davis, DO, medical director at the Hepatitis Treatment Institute of Florida, said there was some outcry from the community on the pricing of these new agents, but both manufacturers have established “aggressive” patient assistance programs.
Vertex’s co-pay assistance covers up to 20% of the total cost of telaprevir for people who pay out-of-pocket or have an insurance co-pay, regardless of household income. If the co-pay is less than the 20% of the prescription price, the drug will be free.
The Vertex Free Medicine Program will provide telaprevir at no cost to people who do not have insurance, are not covered by other benefits programs, and have an annual household income of USD 100,000 or less, according to a company press release.
Merck is offering a discount co-pay card that will allow eligible individuals to save up to USD 200 on up to 12 boceprevir prescriptions for up to 48 weeks, though many people will not need to be treated that long, according to a company press release.
Ultimately, patients don’t care about the total cost, but what their co-pay is, said Dr Paul Pockros, head of the Division of Gastroenterology and Hepatology, Scripps Clinic. Pockros, who has written an estimated 60 prescriptions starting patients on triple therapy, said payers have been reasonable. Dr Melissa Palmer, director of Hepatology at NYU Hepatology Associates, estimated writing nearly 250 prescriptions in total for both drugs, and added she has faced no issues so far with reimbursement.
Dr Doris Strader, associate professor of medicine, Division of Gastroenterology, University of Vermont College of Medicine, estimated a prior authorization period of three to four weeks. Generally, it is slightly longer than the prior authorization period with pegylated-interferon and ribavirin, she noted.
There is a “pretty quick turnaround” from payers with regards to these two new HCV drugs, said Dr Michael Epstein, gastroenterologist and founder of Digestive Disorders Associates in Annapolis, Maryland. He noted that his center often works through specialty benefits pharmacies to take “a lot of the sting” out of the process. Dr Tarek Hassanein, a hepatologist and medical director at Southern California Liver Centers, similarly reported using specialty benefits pharmacies to make the process easier.
A Merck spokesperson said specialty pharmacies have a legacy position in HCV in offering pegylated-interferon and ribavirin, and it is expected they will continue to maintain an important role, with Merck having a long-term strategy to work with that channel.
Payer requirements
Having written 20-30 prescriptions for triple therapy, Hassanein said thus far, only two of his patients have been denied coverage. Those payers did not provide clear reasons for denying coverage, he noted. Davis added he has heard from the community that some payers have chosen to cover one drug but not the other -- although it has not happened in his practice.
Pockros noted he has particularly been having difficulty with Blue Cross of California, which is the biggest payer by volume for his practice. This specific insurance company has been requiring a USD 19,000 co-pay for telaprevir. The Vertex patient assistance program covers roughly USD 10,000, and the remaining difference is still too large of a financial burden to patients. This is in stark contrast to some other payers, which require only a USD 50 monthly co-pay.
“We are putting some of these patients on boceprevir, because it costs less,” Pockros said.
The Merck spokesperson said Victrelis has received a preferred or exclusive position in the formularies of some public payers, based first on its safety and efficacy proposition, followed by its dollar value proposition.
Dr Michael DeMicco, a gastroenterologist with Associated Gastroenterology Medical Group in Anaheim, California, said he has encountered some difficulty with other payers based in California, including Medi-Cal and CalOptima.
Multiple letters detailing how sick the patient is have to be sent, along with their likelihood of developing cirrhosis, a common complication in HCV patients, to get the new drugs approved by these payers, DeMicco explained. These payers have been “very resistant,” he added. However, Dr Sammy Saab, associate clinical professor of medicine, Division of Digestive Diseases and the Division of Liver and Pancreas Transplantation at UCLA, said the specialty pharmacies his center works through have noted that Medi-Cal has been the easiest payer to work with.
Payers have been asking for a baseline viral load and checking the genetic basis of a patient’s disease, said Pockros, as both drugs are currently approved for use only in only some HCV patients, who are classified as Genotype 1. Coverage was denied for off-label use in a Genotype 2 patient, he noted.
Epstein said for each patient, he typically provides payers with a clinical evaluation that was conducted within the last month, the patient’s lab results from the last 90 days and a liver biopsy test from within the past year.
Payers largely have not been asking for any interim treatment data, such as week four HCV RNA viral load, which indicates a patient’s response to treatment, several sources noted, though some mentioned having heard this occurring elsewhere. Ethically, “I don’t know how [payers] can wait for that viral load,” said Palmer, as the time lag could result in a patient missing doses while waiting for additional authorization.
Once prior authorization is received, payers have been deferring to clinician judgment on whether to continue therapy or not, said Strader. For telaprevir, with a total duration of treatment of only 12 weeks, some interim lab results might only be returned after the patient completes treatment, she said. With boceprevir, maybe some interim lab data would be returned while still during the course of treatment.
Praise for HCV patient assistance programs
Both companies have been generous about patient support, said Pockros, particularly for patients that fall in the Medicare Part D “donut hole.” Though his center rarely sees Medicare patients, Davis noted that it is difficult for these patients, as they are unable to pre-pay to gain access to these new drugs, unless they have a secondary pharmaceutical plan.
The prior authorization period can take longer when patients have additional financial concerns, Davis added. Some additional financial paperwork has to be done, which is usually a disclosure the patient makes under a income cap, he said. The companies have not been asking for tax returns in these cases, he added.
Pockros discussed a telaprevir patient who had insurance, but then lost his job two weeks into treatment. By the time the patient notified Pockros, he had only three days to get the patient telaprevir so he would not miss a dose, but the patient’s COBRA insurance still had not gone into effect. Pockros said he was able to contact Vertex, and the company was able to ship the drug to the patient, in order to avoid missing any doses.
Palmer reported a scenario for a boceprevir patient, where the specialty pharmacy did not get the drug to the patient in time, but found that Merck was unable to get drug to the patient in this scenario. She said she brought this situation to Merck directly, and that the company is actively working to get a program in place.
The Merck spokesperson said scenarios like these do happen, which are outside of the company’s control, and the usual process by which a patient receives his/her drug. He said Merck has put into place both supply chain and specialty pharmacy initiatives to try to ensure rapid, immediate, and uninterrupted drug supply, but that “there are always going to be those wrinkles” to the usual process.
Both Pockros and Palmer said they typically keep pegylated-interferon and ribavirin on hand for such scenarios, but that there are currently no samples available for either drug, with physicians left to rely on these gap programs instead.
Vertex could not be reached for comment.
Read More:
http://www.ft.com/intl/cms/s/2/d1970424-d575-11e0-bd7e-00144feab49a,dwp_uuid=e8477cc4-c820-11db-b0dc-000b5df10621.html#axzz1WteuehVo
Patient Assistance Program
INCIVEK/Telaprevir and VICTRELIS (Boceprevir) Patient Assistance Programs
Dermatological side effects-Patient management in the era of direct-acting antivirals
Dermatological side effects of hepatitis c and its treatment: Patient management in the era of direct-acting antivirals
Received 23 June 2011; received in revised form 26 July 2011; accepted 2 August 2011. published online 30 August 2011. Accepted Manuscript
Abstract
Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome.
Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone.
In telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus and eczema).
A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, agroup of rare conditions that are potentially life-threatening. It is therefore important to distinguish between telaprevir-related dermatitis and SCAR. The telaprevir prescribing information does not require telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids.
For Grade 3 rash, the prescribing information mandates immediate telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7 days of stopping telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued.
Blog Note;
SCAR- Severe Cutaneous Adverse Reactions Cutaneous drug reactions occur when your skin has a reaction to a drug.
DRESS-(Drug Reaction with Eosinophilia and Systemic Symptoms) Japanese Dermatologists call this syndrome DIHS (Drug Induced Hypersensitivity Syndrome) while European and American dermatologists suggested the acronym of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)
DRESS is one of several terms that has been used to describe a severe idiosyncratic reaction to a drug that is characterized by a long latency of onset after exposure to the offending medication, a rash, involvement of internal organs, hematologic abnormalities and systemic illness.
Also View;
Hepatitis C Drug Incivek (telaprevir); What are the side effects ?
Use of New HCV Protease Inhibitors ‘Not That Simple’
Received 23 June 2011; received in revised form 26 July 2011; accepted 2 August 2011. published online 30 August 2011. Accepted Manuscript
Abstract
Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome.
Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone.
In telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus and eczema).
A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, agroup of rare conditions that are potentially life-threatening. It is therefore important to distinguish between telaprevir-related dermatitis and SCAR. The telaprevir prescribing information does not require telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids.
For Grade 3 rash, the prescribing information mandates immediate telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7 days of stopping telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued.
Blog Note;
SCAR- Severe Cutaneous Adverse Reactions Cutaneous drug reactions occur when your skin has a reaction to a drug.
DRESS-(Drug Reaction with Eosinophilia and Systemic Symptoms) Japanese Dermatologists call this syndrome DIHS (Drug Induced Hypersensitivity Syndrome) while European and American dermatologists suggested the acronym of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)
DRESS is one of several terms that has been used to describe a severe idiosyncratic reaction to a drug that is characterized by a long latency of onset after exposure to the offending medication, a rash, involvement of internal organs, hematologic abnormalities and systemic illness.
Also View;
Hepatitis C Drug Incivek (telaprevir); What are the side effects ?
Use of New HCV Protease Inhibitors ‘Not That Simple’
Chronic fatigue syndrome - In support of XMRV researchers
In support of XMRV researchers
Posted on September 2nd, 2011
by PLoS ONE Editors
Chronic fatigue syndrome (CFS) is a mysterious condition. Its cause, diagnosis, even its name have long been sources of controversy, and it appears that this controversy has recently reached new heights, with some individuals issuing a series of threats to a subset of researchers in the field, as reported in a recent article in the Observer.
This particular episode of the conflict involves a paper published in PLoS ONE in Jan. 2010, so we feel at this point it is appropriate for us to comment and express our disapproval of this behavior.
The PLoS ONE study was the first response to an Oct. 2009 article in the journal Science that reported a correlation between CFS and a virus called XMRV. Contrary to the original finding, the PLoS ONE paper reported no evidence of XMRV in CFS patients, and a number of similar studies followed on its heels (see examples here and here), prompting Science to issue an expression of concern.
These later reports generated a very negative response from some individuals at the time of publication – a number of comments on the PLoS ONE paper had to be removed from the website because of inappropriate content – and it appears that the situation has not improved. According to the Observer article, “the militants are now considered to be as dangerous and uncompromising as animal rights extremists.” The article goes on to describe various instances of physical and verbal abuses, including daily death threats addressed to the lead author of the PLoS ONE paper, Professor Myra McClure.
As the debate about CFS continues, we at PLoS would like to take the opportunity to express support for our authors and for their right, and of course everyone else’s right, to enjoy the freedom to debate and investigate scientific topics openly, constructively, and without fear. This situation has emphasized, to us, the importance of civilized discourse in these matters. Those who threaten researchers’ safety above all do themselves a major disservice by dissuading other researchers from entering the field, chasing away the very people who may be able to help them. It is bad both for science and for patients, and should absolutely not be tolerated.
http://blogs.plos.org/everyone/2011/09/02/in-support-of-xmrv-researchers/
Posted on September 2nd, 2011
by PLoS ONE Editors
Chronic fatigue syndrome (CFS) is a mysterious condition. Its cause, diagnosis, even its name have long been sources of controversy, and it appears that this controversy has recently reached new heights, with some individuals issuing a series of threats to a subset of researchers in the field, as reported in a recent article in the Observer.
This particular episode of the conflict involves a paper published in PLoS ONE in Jan. 2010, so we feel at this point it is appropriate for us to comment and express our disapproval of this behavior.
The PLoS ONE study was the first response to an Oct. 2009 article in the journal Science that reported a correlation between CFS and a virus called XMRV. Contrary to the original finding, the PLoS ONE paper reported no evidence of XMRV in CFS patients, and a number of similar studies followed on its heels (see examples here and here), prompting Science to issue an expression of concern.
These later reports generated a very negative response from some individuals at the time of publication – a number of comments on the PLoS ONE paper had to be removed from the website because of inappropriate content – and it appears that the situation has not improved. According to the Observer article, “the militants are now considered to be as dangerous and uncompromising as animal rights extremists.” The article goes on to describe various instances of physical and verbal abuses, including daily death threats addressed to the lead author of the PLoS ONE paper, Professor Myra McClure.
As the debate about CFS continues, we at PLoS would like to take the opportunity to express support for our authors and for their right, and of course everyone else’s right, to enjoy the freedom to debate and investigate scientific topics openly, constructively, and without fear. This situation has emphasized, to us, the importance of civilized discourse in these matters. Those who threaten researchers’ safety above all do themselves a major disservice by dissuading other researchers from entering the field, chasing away the very people who may be able to help them. It is bad both for science and for patients, and should absolutely not be tolerated.
http://blogs.plos.org/everyone/2011/09/02/in-support-of-xmrv-researchers/
Friday, September 2, 2011
New Options for HCV Treatment: Is Better Good Enough?
New Options for HCV Treatment: Is Better Good Enough?
Published Aug 8th, updated August 22, 2011
The Experts Respond
Two experts describe how they would manage our latest Antiretroviral Rounds case.
We recently asked whether you would recommend new hepatitis C virus (HCV) treatment options to an HIV/HCV-coinfected patient who had only a partial response, as well as treatment-limiting adverse effects, on prior peginterferon/ribavirin therapy. Now, two experts describe what they would do.
The Case
A 62-year-old man with HIV/HCV genotype 1b coinfection and a remote history of injection-drug use is seen for follow-up to discuss the new treatment options for HCV. He has been on HIV treatment since 1998 and is currently stable on tenofovir/FTC + lopinavir/ritonavir, with a CD4 count of 550 cells/mm3 and an undetectable HIV viral load. He has severe lipoatrophy, presumably as a result of prior treatment with d4T + 3TC, which was given initially as dual therapy and then in combination with indinavir.
He underwent a liver biopsy in 2004 that demonstrated mild portal fibrosis, with few septa and no bridging (Metavir score F2). In 2008, he received peginterferon/ribavirin with appropriate weight-based dosing; at baseline, the HCV RNA level was 7.5 million copies/mL. Within 4 weeks of starting treatment, he had a 2-log decline in HCV RNA, but by 6 months, the HCV RNA was still detectable, at 2600 copies/mL. In addition, he reported several side effects — all of which worsened over time — including severe fatigue, taste disturbance, irritability, and difficulty completing his daily work responsibilities. Most concerning to him, however, was a 10-lb weight loss that made his lipoatrophy much more prominent. The HCV treatment was discontinued, and his symptoms soon resolved.
The patient now comes to the clinic saying he has heard of the new HCV treatment options and wonders whether you would recommend them. He is extremely concerned about side effects and worries that his job might be in jeopardy if he could not work at full capacity.
Tell Us What You Would Do
Would you offer this patient repeat treatment, with interferon/ribavirin + telaprevir or boceprevir? Would you do additional assessments to make this decision, such as repeat liver biopsy, interleukin (IL)-28B genotype, or other noninvasive tests of liver injury? If you decide not to treat him, what would be your major reason or reasons?
If you do treat him:
Which of the new drugs would you prescribe?
What would you cite as the likelihood of cure?
How would you alter the patient's HIV treatment?
How would you plan to manage the side effects of HCV treatment?
Response 1
— Barbara H. McGovern, MD
There are many reasons to hold off on triple therapy here, including the absence of data from treatment-experienced HIV/HCV-coinfected patients and the risk for side effects that could compromise the patient's job performance. However, I would consider such therapy sooner rather than later if I knew that the patient's underlying liver disease had progressed beyond the mild portal fibrosis seen in 2004. To evaluate this possibility,
I would look for evidence of stable disease, using a noninvasive fibrosis marker. If the fibrosis marker is concordant with the earlier biopsy results, I would counsel the patient to wait on retreatment until more information becomes available on the optimal approach. In the event of discordant findings, I would consider a repeat liver biopsy, because the clinical path ahead is so uncertain.
If the liver biopsy confirms progression to bridging fibrosis or cirrhosis, I would recommend peginterferon/ribavirin + telaprevir for 12 weeks, followed by peginterferon/ribavirin alone for an additional 36 weeks. This approach should give the patient a 40% to 50% percent chance of achieving a sustained virologic response (SVR), based on extrapolation of data from HCV-monoinfected patients (N Engl J Med 2011; 364:2417). Lack of response would put the patient at risk for development of drug resistance, although the long-term clinical implications of such resistance are unclear.
The IL-28B assay is a powerful pretreatment predictor of treatment outcome, but I would not order it for this patient because we already know how he responded to interferon in the past.
Of the two available HCV protease inhibitors, I would consider only telaprevir, because we have pharmacokinetic data on drug–drug interactions to help guide our therapeutic decisions. For example, we know that telaprevir interacts negatively with lopinavir/ritonavir, so I would recommend switching the lopinavir/r in this patient's regimen to either efavirenz or boosted atazanavir (Abstract 119, CROI 2011). If efavirenz is selected, telaprevir dosing would need to be increased (Abstract 146LB, CROI 2011).
Mild-to-moderate rash is seen in approximately half of all patients taking telaprevir, so I would start the patient's new antiretroviral regimen about 4 to 6 weeks before the HCV therapy, to sort out any untoward reactions. I would counsel the patient about the importance of strict medication adherence and the need to take telaprevir according to schedule with a fatty snack (e.g., peanut butter, whole-milk yogurt).
Response 2
— Arthur Y. Kim, MD
Although this patient had only a partial response to prior peginterferon/ribavirin therapy, he does have a chance at an SVR with novel regimens. Having genotype 1b (rather than 1a) infection works slightly in his favor, because this virus does not readily develop a key resistance mutation to protease inhibitors. Barriers to successful treatment, however, include his high HCV RNA level, the HIV coinfection, and, most importantly, the severe and lifestyle-altering side effects he experienced during previous therapy, which are now reducing his motivation to be treated. Given the high likelihood that these side effects will happen again with retreatment, I would advise him to wait for interferon-sparing regimens — unless he has advancing liver fibrosis.
Although this patient has probably had HCV for decades, his fibrosis still could have advanced considerably since his 2004 biopsy; in several studies, serial biopsies performed over short periods have shown significant progression of fibrosis despite stable HIV disease (AIDS 2007; 21:2209 and Hepatology 2009; 50:1056). To look for signs of advancing liver disease in this patient, I would first perform a careful physical examination and laboratory review. Next, I would restage him, preferably using liver biopsy rather than noninvasive testing, to allow direct comparison with the data we have available from 2004. Predictive IL-28B genetic testing seems unnecessary given that we already know the patient's biological responsiveness to peginterferon/ribavirin (i.e., the previous viral kinetics on treatment).
If I were to treat this patient with combination therapy, I would use telaprevir rather than boceprevir because data are available on its safety and efficacy in HIV/HCV-coinfected patients (Abstract 146LB, CROI 2011). Unfortunately, these data do not extend to coinfected patients with prior HCV treatment experience, so predicting the likelihood of an SVR in this patient is difficult. In monoinfected patients with prior partial response to peginterferon/ribavirin, the SVR rate associated with novel treatments exceeds 50%. I would inform the patient that the rate of response to HCV treatment is generally lower in HIV-coinfected than HCV-monoinfected patients, without quoting an exact number. In terms of managing his HIV treatment alongside the new HCV therapy, I would change his lopinavir/r to either boosted atazanavir or efavirenz (barring evidence of resistance or prior adverse effects), to mimic the regimens used in the telaprevir trial presented at CROI this year.
Dr. McGovern is Associate Professor of Medicine in the Division of Infectious Diseases at Tufts University School of Medicine and Director of the Viral Hepatitis Clinic at Lemuel Shattuck Hospital in Boston. She reports no conflicts of interest.
Dr. Kim is Assistant Professor of Medicine at Harvard Medical School and Director of the Viral Hepatitis Clinic (Infectious Diseases) at Massachusetts General Hospital in Boston. He reports no conflicts of interest.
Published in Journal Watch HIV/AIDS Clinical Care August 22, 2011
Published Aug 8th, updated August 22, 2011
The Experts Respond
Two experts describe how they would manage our latest Antiretroviral Rounds case.
We recently asked whether you would recommend new hepatitis C virus (HCV) treatment options to an HIV/HCV-coinfected patient who had only a partial response, as well as treatment-limiting adverse effects, on prior peginterferon/ribavirin therapy. Now, two experts describe what they would do.
The Case
A 62-year-old man with HIV/HCV genotype 1b coinfection and a remote history of injection-drug use is seen for follow-up to discuss the new treatment options for HCV. He has been on HIV treatment since 1998 and is currently stable on tenofovir/FTC + lopinavir/ritonavir, with a CD4 count of 550 cells/mm3 and an undetectable HIV viral load. He has severe lipoatrophy, presumably as a result of prior treatment with d4T + 3TC, which was given initially as dual therapy and then in combination with indinavir.
He underwent a liver biopsy in 2004 that demonstrated mild portal fibrosis, with few septa and no bridging (Metavir score F2). In 2008, he received peginterferon/ribavirin with appropriate weight-based dosing; at baseline, the HCV RNA level was 7.5 million copies/mL. Within 4 weeks of starting treatment, he had a 2-log decline in HCV RNA, but by 6 months, the HCV RNA was still detectable, at 2600 copies/mL. In addition, he reported several side effects — all of which worsened over time — including severe fatigue, taste disturbance, irritability, and difficulty completing his daily work responsibilities. Most concerning to him, however, was a 10-lb weight loss that made his lipoatrophy much more prominent. The HCV treatment was discontinued, and his symptoms soon resolved.
The patient now comes to the clinic saying he has heard of the new HCV treatment options and wonders whether you would recommend them. He is extremely concerned about side effects and worries that his job might be in jeopardy if he could not work at full capacity.
Tell Us What You Would Do
Would you offer this patient repeat treatment, with interferon/ribavirin + telaprevir or boceprevir? Would you do additional assessments to make this decision, such as repeat liver biopsy, interleukin (IL)-28B genotype, or other noninvasive tests of liver injury? If you decide not to treat him, what would be your major reason or reasons?
If you do treat him:
Which of the new drugs would you prescribe?
What would you cite as the likelihood of cure?
How would you alter the patient's HIV treatment?
How would you plan to manage the side effects of HCV treatment?
Response 1
— Barbara H. McGovern, MD
There are many reasons to hold off on triple therapy here, including the absence of data from treatment-experienced HIV/HCV-coinfected patients and the risk for side effects that could compromise the patient's job performance. However, I would consider such therapy sooner rather than later if I knew that the patient's underlying liver disease had progressed beyond the mild portal fibrosis seen in 2004. To evaluate this possibility,
I would look for evidence of stable disease, using a noninvasive fibrosis marker. If the fibrosis marker is concordant with the earlier biopsy results, I would counsel the patient to wait on retreatment until more information becomes available on the optimal approach. In the event of discordant findings, I would consider a repeat liver biopsy, because the clinical path ahead is so uncertain.
If the liver biopsy confirms progression to bridging fibrosis or cirrhosis, I would recommend peginterferon/ribavirin + telaprevir for 12 weeks, followed by peginterferon/ribavirin alone for an additional 36 weeks. This approach should give the patient a 40% to 50% percent chance of achieving a sustained virologic response (SVR), based on extrapolation of data from HCV-monoinfected patients (N Engl J Med 2011; 364:2417). Lack of response would put the patient at risk for development of drug resistance, although the long-term clinical implications of such resistance are unclear.
The IL-28B assay is a powerful pretreatment predictor of treatment outcome, but I would not order it for this patient because we already know how he responded to interferon in the past.
Of the two available HCV protease inhibitors, I would consider only telaprevir, because we have pharmacokinetic data on drug–drug interactions to help guide our therapeutic decisions. For example, we know that telaprevir interacts negatively with lopinavir/ritonavir, so I would recommend switching the lopinavir/r in this patient's regimen to either efavirenz or boosted atazanavir (Abstract 119, CROI 2011). If efavirenz is selected, telaprevir dosing would need to be increased (Abstract 146LB, CROI 2011).
Mild-to-moderate rash is seen in approximately half of all patients taking telaprevir, so I would start the patient's new antiretroviral regimen about 4 to 6 weeks before the HCV therapy, to sort out any untoward reactions. I would counsel the patient about the importance of strict medication adherence and the need to take telaprevir according to schedule with a fatty snack (e.g., peanut butter, whole-milk yogurt).
Response 2
— Arthur Y. Kim, MD
Although this patient had only a partial response to prior peginterferon/ribavirin therapy, he does have a chance at an SVR with novel regimens. Having genotype 1b (rather than 1a) infection works slightly in his favor, because this virus does not readily develop a key resistance mutation to protease inhibitors. Barriers to successful treatment, however, include his high HCV RNA level, the HIV coinfection, and, most importantly, the severe and lifestyle-altering side effects he experienced during previous therapy, which are now reducing his motivation to be treated. Given the high likelihood that these side effects will happen again with retreatment, I would advise him to wait for interferon-sparing regimens — unless he has advancing liver fibrosis.
Although this patient has probably had HCV for decades, his fibrosis still could have advanced considerably since his 2004 biopsy; in several studies, serial biopsies performed over short periods have shown significant progression of fibrosis despite stable HIV disease (AIDS 2007; 21:2209 and Hepatology 2009; 50:1056). To look for signs of advancing liver disease in this patient, I would first perform a careful physical examination and laboratory review. Next, I would restage him, preferably using liver biopsy rather than noninvasive testing, to allow direct comparison with the data we have available from 2004. Predictive IL-28B genetic testing seems unnecessary given that we already know the patient's biological responsiveness to peginterferon/ribavirin (i.e., the previous viral kinetics on treatment).
If I were to treat this patient with combination therapy, I would use telaprevir rather than boceprevir because data are available on its safety and efficacy in HIV/HCV-coinfected patients (Abstract 146LB, CROI 2011). Unfortunately, these data do not extend to coinfected patients with prior HCV treatment experience, so predicting the likelihood of an SVR in this patient is difficult. In monoinfected patients with prior partial response to peginterferon/ribavirin, the SVR rate associated with novel treatments exceeds 50%. I would inform the patient that the rate of response to HCV treatment is generally lower in HIV-coinfected than HCV-monoinfected patients, without quoting an exact number. In terms of managing his HIV treatment alongside the new HCV therapy, I would change his lopinavir/r to either boosted atazanavir or efavirenz (barring evidence of resistance or prior adverse effects), to mimic the regimens used in the telaprevir trial presented at CROI this year.
Dr. McGovern is Associate Professor of Medicine in the Division of Infectious Diseases at Tufts University School of Medicine and Director of the Viral Hepatitis Clinic at Lemuel Shattuck Hospital in Boston. She reports no conflicts of interest.
Dr. Kim is Assistant Professor of Medicine at Harvard Medical School and Director of the Viral Hepatitis Clinic (Infectious Diseases) at Massachusetts General Hospital in Boston. He reports no conflicts of interest.
Published in Journal Watch HIV/AIDS Clinical Care August 22, 2011
New Sweat Sensors for Detecting Low Blood Glucose Levels
UNNOTICEABLE SWEAT: "Even simple mental arithmetic can have a big impact on the sweat meter," says scientist Christian Tronstad (right). Photo: Yngve Vogt
New Sweat Sensors for Detecting Low Blood Glucose Levels and Other Conditions
A new sweat meter developed at University of Oslo and the National Hospital of Norway may provide diabetics a non-invasive way to detect low blood sugar levels. There’s a noticeable change in sweat patterns when blood glucose approaches dangerously low levels, hence there is hope that the new technology will be sensitive enough to become a preemptive tool to avoid clinically significant hypoglycemia.
The researchers are now preparing for clinical testing of the new devices on diabetic patients, and other groups are finding use for the sweat sensors for studying kids with chronic fatigue syndrome and night sweats.
Video;Dr. Fauci on 30 years of AIDS
NIAID Director Dr. Tony Fauci discusses the history of HIV/AIDS in the U.S
Date: 01 Sep 2011 Length: 47m 8s
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