Blood Sample Bill a Bad Idea: BC Health Officer

Emergency workers exposed to bodily fluids have better protections: Kendall.

By Andrew MacLeod, Yesterday, TheTyee.ca

Provincial Health Officer Perry Kendall has sent a letter to all British Columbia MLAs advising them against voting for a bill aimed at helping people who respond to emergencies.

The bill won't succeed at preventing any infections as it intended to, and it may well increase the risk, he said.

The Emergency Intervention Disclosure Act would allow police, firefighters and paramedics to use a court order to force someone to give a blood sample if they've been exposed to that person's bodily fluids during the course of their work.

Labour, Citizens' Services and Open Government Minister Margaret MacDiarmid, who worked as a family physician before entering politics, introduced the bill on April 30. Both government and opposition MLAs have expressed support for the bill, while noting the concerns raised by Kendall and Information and Privacy Commissioner Elizabeth Denham.

"I fully recognize that elected officials have the final authority over what they choose to enact legislatively," Kendall wrote in his May 1 letter. "But I respectfully submit that there are some substantive public health and policy issues that may not have been fully appreciated in discussions so far. I am setting out my concerns in order to ensure that your decisions may be fully informed."

No infection reduction

Kendall began by saying he has "nothing but respect" for first responders and that he recognizes the risk their work brings of exposure to blood and bodily fluids that may contain pathogens, and the anxiety those exposures can bring.

But after four pages bringing a medical perspective to the question, he concluded, "It should be apparent that the actions available under this proposed Act will in no way reduce the risk of infection or result in any fewer episodes of occupational disease transmission."

Moreover, he said, "A case could be made that passage of the Act could result in increasing such risk if an exposed First Responder relied upon knowing the infection status of the source prior to initiating post-exposure prophylaxis."

The main concerns are HIV, hepatitis B and hepatitis C, he said. "There is an alternative resolution to these concerns that obviates the need to seek a court order overruling an individual's right to refuse to submit to diagnostic testing, and alternative that has a lower likelihood of unwanted adverse consequences."

There is a vaccine for hepatitis B that all first responders should have, he said. If they are exposed, they should take immune globulin, which "virtually guarantees 100 per cent protection from recent and future exposures."

Better options for treatment

In the case of HIV, the treatment should start much quicker than the time it would take to force and get a blood test, Kendall said.

"Post-exposure prophylaxis is highly effective and with newer medications, well-tolerated, should be started within two hours, and is recommended to continue for 28 days," he said. "Waiting for test results from a source person could result in a preventable HIV infection occurring, and even a negative test result of a high risk source does not guarantee that the source is not infected due to the possibility of false negative tests."

As for hepatitis C, there is no vaccine or prophylaxis available. "Post-exposure management recommends follow up to ascertain whether infection has occurred and to institute antiviral therapy if so confirmed," Kendall wrote.

The letter notes that WorkSafeBC figures show that since 1987 there have been 47 cases the agency has followed where first responders have been exposed to blood.

"There is thus a statistically small, but very real risk, and that must be taken seriously," said Kendall. "I suggest that addressing this risk can better be done by ensuring that first responders are educated about, have access to, and utilize universal precautions, pre-exposure prophylaxis where applicable, the most up-to-date diagnostic testing technologies and evidence-based post-exposure follow up."

With the most recent testing technology, known as Polymerase Chain Reaction, an infection can be found within the first responders' own blood within two weeks, Kendall said in a May 4 interview.

Forcing a person to give a sample through a court order under the proposed law would require would likely take longer, he said. "It's hard to imagine this happening in a period of time that's less than two weeks."

Practice won't change: MacDiarmid

A new generation of testing that will give results quicker is on its way, but is not yet commonly available, said Minister MacDiarmid. "We're not there at this point."

The new law will not replace the current practice, she said. "They still take all the precautionary steps."

First responders do take precautions to prevent exposure to people's bodily fluids, but it's not always possible, she said, giving the example of a paramedic arriving at a car wreck who cuts himself badly while reaching in to help someone in the vehicle.

It's also standard to go on a prophylactic treatment right away when there's been an exposure, she said.

But first responders have said they want the peace of mind a law like the one B.C. is debating would bring, she said. "I think it's really hard to dismiss that... To say there's no benefit at all, I find that quite difficult."

In most cases people will give a sample willingly, but for those rare times when they won't first responders would like to be able to compel them, she said. In Alberta, which has a similar law, it has only been used twice, she said.

"We do recognize if someone doesn't want to reveal that information, there's a privacy element to it," she said. "It's a place where we've tried to find a balance."

The majority of the MLAs support passing the bill, she said.

Support for first responders, says NDP

Indeed, when the bill came up for second reading debate on the morning of May 3, three NDP MLAs acknowledged the concerns outlined in Kendall's letter, but said they would support the bill regardless.

They included Michelle Mungall from Nelson-Creston, Jagrup Brar from Surrey-Fleetwood and health critic Mike Farnworth.

"I think it's important that we do address some of the issues [Kendall] has raised in committee stage of the bill," said Farnworth, according to Hansard. "But I think, on balance, this is a bill that strikes just that -- the right balance between the needs of our first responders in this province and the issues around privacy. I think this bill does achieve that balance, and that's why I'm pleased to support it."

The bill sends a "strong message to first responders" in the province, he said, "that members of this House have been listening to their concerns and have put forward a piece of legislation that I think meets those needs. At the end of the day, that should be what governing is about."

Certainly the bill has the support of first responders. At least a dozen, in uniform, were in MacDiarmid's office the day she introduced the bill, and reporters received printed testimonials from 14 across the province who had been exposed to bodily fluids while on the job.

One, for example, was from Lee DePellegrin, the president of the Trail Fire Fighters, who told of a colleague who while at the station had a man spit "blood and bodily fluids" in his unprotected face. The fire fighter got treatment, but didn't have peace of mind, he said. "Although the prophylactic treatment was the responsible course of action in this case, there was and is always a doubt etched in the back of the fire fighter's mind about whether he was actually exposed to a communicable disease or not."

If the person who spat at the fire fighter had been confirmed to have an infection, "then the appropriate specific treatment for the type of exposure could have been administered, as opposed to the general prophylactic cocktail," DePellegrin said.

Had the person tested negative, "a treatment may very well have happened anyway, but the big difference is the fire fighter would have confidence that after the treatment and subsequent tests, they could live a life without doubts and fear."

Provincial Health Officer Kendall, however, pointed out that sense of reassurance may be misplaced. "It won't reduce infection," he said. "The only benefit of the knowledge would be if you could get it in time and you trusted it."

In the case of HIV, for example, knowing a person didn't have it might allow the first responder to stop taking the drug therapy sooner or to return to having sex without a condom with a regular partner. However, there's a "window period" where an infected person won't test positive, so it would not be advisable to trust that first test, he said.

The government's bill is well intentioned, he said. "For all its good intentions, it may well have negative side effects that outweigh those good intentions."

Kendall in his letter also said the bill also "carries with it the spectre of possible re-exacerbation of AIDS phobia, and the further stigmatization of certain classes of individuals."

Information and Privacy Commissioner Elizabeth Denham last week wrote to MacDiarmid saying the small benefit from the bill does not outweigh the privacy invasion of requiring a medical test, The Tyee reported. "[It] subjects individuals to a process of looking for disease that is highly privacy invasive while providing little to no demonstrable benefit to the emergency responder," she said.

Andrew MacLeod is The Tyee's Legislative Bureau Chief in Victoria. Find him on Twitter or reach him here.

Source

New Drugs Require New Terms for HCV Virologic Response

From Medscape Medical News

Daniel M. Keller, PhD

May 8, 2012 (Barcelona, Spain) — The development of drugs to treat hepatitis C virus (HCV) is progressing rapidly, but the terminology to quantify virologic response is lagging. A consortium of interested organizations is creating nomenclature for virologic responses in trials of direct-acting antiviral drugs, which are small-molecule inhibitors of viral enzymes that hold the promise of interferon-free treatment regimens.

During a poster session here at the International Liver Congress 2012, Donald Jensen, MD, professor of medicine at the University of Chicago Medical Center in Illinois, presented the rationale for and principles of the nomenclature being developed by the Hepatitis C Virus Drug Development Advisory Group (HCV DrAG).

HCV DrAG is a project of the Forum for Collaborative HIV Research, which has a subgroup devoted to HCV research with experts from the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver (EASL), and the Infectious Diseases Society of America. The forum is a broad consensus panel that includes industry representatives, members of American and European drug regulatory agencies, academic investigators, and representatives of advocacy groups.

Direct-acting antiviral drugs have potent antiviral actions and appear to produce a more rapid virologic response, with or without interferon, than interferon-based regimens without the new drugs. More intuitive and flexible virologic measures are needed that can adapt to these advances in HCV treatment.

"We wanted to do this before all the new oral therapies hit the market," Dr. Jensen told Medscape Medical News.

He said current terminology can be confusing when describing virologic response to the new therapies. "We felt that there was a need to have this description of virologic responses more consistent across studies — something that could also be used in manuscripts and in clinical practice," he said. A panel of experts set out to develop a nomenclature "that was intuitive, that made sense, and that was descriptive of virologic responses during the course of therapy for hepatitis C."

Considerations for Nomenclature Development

Comparisons between drugs or regimens is difficult or impossible without a common nomenclature. The propsed nomenclature will assign a description of the time frame and the level of response to the measures, as opposed to a qualitative description such as "rapid virologic response."

The proposed terminology for key decision points in treatment trials takes into account the assay-specific lower limits of quantification of HCV RNA (as opposed to lower limits of detection), with responses defined as quantifiable or unquantifiable levels of HCV RNA.

Key components in expressing virologic response are the week of treatment, the quantifiable decline in viral load from initiation of treatment (expressed as log₁₀ decline), any lead-in treatment duration (days or weeks), and whether the target HCV RNA was detected or not. The panel explains that the lower limit of quantitation (LLOQ) of a virologic assay should be clearly specified. (One common problem in current trials is the use of different commercial assay systems.) The target may or may not be detected at levels below the LLOQ.

HCV viremia at levels less than the LLOQ in trials without a lead-in treatment period — what has been called a rapid virologic response — would now be W4U, meaning an unquantifiable HCV RNA level at week 4, whether detectable or undetectable. The old complete early virologic response will now be W12U, denoting a week 12 unquantifiable HCV RNA level.

For trials with a lead-in (LI) period at, for example, weeks 0 to 4, and unquantifiable levels at week 8 (the old rapid virologic response), the new nomenclature would specifically refer to it as LI_4w-W8U. Each term would be appended with TD or TND to denote whether target HCV RNA was detected or not detected.

One holdover from the current system is sustained virologic response (SVR).

"We decided to keep SVR...but it will be sustained virologic response with a bracket after it" to denote how long the response has been sustained, Dr. Jensen noted. "We're going to keep [it] because I think that's a concept that will be consistent with future therapies."

Having a uniform reporting system will allow the comparison of results across clinical trials. In addition, the system will be able to adapt as virologic response times become shorter. Beyond clinical trials, specific terminology will aid in the development of treatment guidelines for clinical practice.

The panel has submitted a manuscript for publication. Dr. Jensen hopes that industry will adopt the system for their clinical trials and that journals will require the system as the accepted nomenclature. The US Food and Drug Administration and the European Medicines Agency, as part of the HCV DrAG working group, have stated that they would like the nomenclature to be adopted.

Dr. Jensen predicts that in the future, if very effective drugs come along and therapy becomes standardized, many of the current or proposed measures of virologic response will go by the wayside, and patients will be treated with a fixed course of therapy with an expectation of cure, as is now common with antibiotics for many infections.

George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital in Athens, Greece, and member of the EASL Governing Board Scientific Committee, told Medscape Medical News that he would like to see a consensus terminology adopted, but he does not expect that it will happen soon.

Nomenclature is not the only problem in defining a response, Dr. Papatheodoridis noted.

He referred to a presentation at the congress in which researchers found a discrepancy in the viral levels of 28% of the more than 1000 samples tested with a new polymerase chain reaction (PCR) assay and the original PCR assay. With the original assay, 75% of samples had undetectable HCV DNA; with the new assay, only about 50% did. Such a difference might be reflected in the "response-guided therapy we're using now with the telaprevir or boceprevir combination," he said.

With the drugs currently in development, the companies decide which assays to use to report their findings. "All the trials are controlled by the companies. They are not controlled by us," Dr. Papatheodoridis explained.

"Another problem, which is very relevant in clinical practice, is the timing of the HCV RNA determination," Dr. Papatheodoridis explained. We don't know if a difference of a few days is relevant. If you have some new excellent drug that achieves a 100% SVR 100%, you don't care, but these are not yet available.

Mark Thursz, MBBS, MD, professor of hepatology in the Department of Medicine at Imperial College London, United Kingdom and secretary general of EASL, agreed that measures of virologic response designed for interferon-based regimens are inadequate in an era of direct-acting antiviral drugs, "because the dynamics are much quicker now. A new set of specific targets are going to be really important when we assess how well the new drugs are working."

Dr. Jensen, Dr. Papatheodoridis, and Dr. Thursz have disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 897. Presented April 20, 2012.

Source

Is there still a role for liver biopsy in managing hepatitis C virus infections?

Clinical Liver Disease

Volume 1, Issue 2, pages 32–35, April 2012

Review

Syed-Mohammed R. Jafri M.D.^*, Stuart C. Gordon M.D.

Article first published online: 26 APR 2012

DOI: 10.1002/cld.30

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

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A2M, alpha-2-macroglobulin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BOC44, boceprevir for 44 weeks; BOC RGT, boceprevir and response-guided therapy; CDS, cirrhosis discriminant score; DAA, direct-acting antiviral; GGT, gamma-glutamyl transpeptidase; HA, hyaluronic acid; INR, international normalized ratio; ITT, intention to treat; Pbo, placebo; PIIINP, amino-terminal propeptide of type III collagen; PR48, peginterferon/ribavirin for 48 weeks; SVR, sustained virological response; T12PR, telaprevir for 12 weeks and peginterferon/ribavirin; T12/PR48, telaprevir for 12 weeks and peginterferon/ribavirin for 48 weeks; TIMP1, tissue inhibitor of metalloproteinase 1.

Current guidelines emphasize the importance of liver biopsy in the management of patients with hepatitis C because liver histology provides patients and their physicians with important prognostic information and helps to guide therapy decisions and treatment regimens.1,2 Recent improvements in antiviral therapy along with the development of alternate modes of evaluating fibrosis have led to a global reassessment of the risks and benefits and the overall wisdom of performing liver biopsy in these patients.

The presence of advanced or worsening fibrosis has traditionally served as an unequivocal indication for therapy,3 and clinicians still use the degree of fibrosis as a means for justifying therapy sooner rather than later. The availability of direct-acting antiviral (DAA) agents, which bring the promise of rapid viral negativity with therapy, intuitively appears to lessen the need for biopsy in therapeutic decision making; this is analogous to previously held perceptions about genotype 2/3 patients, who had higher sustained virological response (SVR) rates. Because of the increased efficacy of the newer regimens and even better regimens around the corner, clinicians and patients may choose to forgo biopsy with the compelling argument that the benefits of such effective therapy justify its use, even in those with minimal disease.

On the basis of the results of pivotal registration trials, the US Food and Drug Administration has suggested that therapy with DAA agents mandates an assessment of the degree of fibrosis because of the vastly different therapeutic regimens for patients with more advanced fibrosis. The recommended treatment with peginterferon/ribavirin and either telaprevir or boceprevir must be longer (48 weeks) because of the consistently lower efficacy of the therapy in patients with cirrhosis2 (Figs. 1–3). Accordingly, an assessment of the degree of fibrosis is crucial before the initiation of therapy. Treatment with interferon and ribavirin has led to higher rates of adverse events, including anemia, in the face of cirrhosis,8,9 and this information must be discussed with patients with cirrhosis before the initiation of current DAA-based therapies that include peginterferon and ribavirin.

Figure 1. SVR rates by the degree of fibrosis in the ADVANCE and ILLUMINATE studies. Abbreviations: ITT, intention to treat; PR48, peginterferon/ribavirin for 48 weeks; T12PR, telaprevir for 12 weeks and peginterferon/ribavirin. Adapted with permission from New England Journal of Medicine.4, 5

Figure 2. SVR rates for patients with bridging fibrosis or cirrhosis in the Serine Protease Inhibitor Therapy 2 trial. Abbreviations: BOC44, boceprevir for 44 weeks; BOC RGT, boceprevir and response-guided therapy; PR48, peginterferon/ribavirin for 48 weeks. Adapted with permission from Journal of Hepatology.6

Figure 3. SVR rates by the degree of fibrosis in the REALIZE trial. Abbreviations: Pbo, placebo; PR48, peginterferon/ribavirin for 48 weeks; T12/PR48, telaprevir for 12 weeks and peginterferon/ribavirin for 48 weeks. Adapted with permission from the European Association for the Study of the Liver.7

In comparison with peginterferon/ribavirin dual therapy, the telaprevir- and boceprevir-based regimens have superior efficacy,4,10-14 but the field is moving forward quite rapidly, and we are currently learning about (1) far more potent DAA agents with better pharmacokinetic profiles, (2) interferon-sparing regiments, and (3) SVR rates approaching 100%. Thus, there is the likelihood that superior regimens will become available over the next few years. As physicians and patients with hepatitis C virus ponder their options, information obtained from liver biopsy samples may greatly assist in the decision to wait yet longer for future regimens with improved efficacy, shorter durations, and lower side-effect profiles.

The establishment of the fibrosis stage remains a key parameter that guides the management of patients with chronic hepatitis C. The presence of advanced fibrosis requires future lifelong screening for the development of varices and hepatocellular carcinoma, regardless of future responses to antiviral therapy. Unfortunately, an all-too-common scenario in clinical practice is the patient with known or unknown hepatitis C who learns of his cirrhosis only after the discovery of liver cancer or a large variceal bleed. Advanced fibrosis may exist in patients with normal liver enzyme levels and synthetic parameters.15 The identification of fibrosis at biopsy can be used as a realistic justification for encouraging reduced alcohol intake and weight reduction, which are factors that would otherwise accelerate the progression to cirrhosis.16-21

For the post–liver transplant patient with chronic hepatitis C, liver biopsy information is essential not only for assessing patients for fibrosis but also for differentiating between recurrent hepatitis C–induced inflammation and acute cellular rejection. Accelerated fibrosis progression in the posttransplant patient with chronic hepatitis C leads to graft loss in up to 30% of infected patients.22-24 Preemptive antiviral therapy without the guidance of biopsy information is often precluded by cytopenias, renal insufficiency, increased side effects, and the possibility of rejection.25,26 Current guidelines suggest the initiation of therapy only after the demonstration of significant cholestasis or fibrosis on liver biopsy.1,27 Accordingly, the information gained from liver biopsy, including the demonstration of either fibrosis progression or a lack of rejection, before the institution of antiviral therapy is vital to the posttransplant care of the hepatitis C patient.

The risks of liver biopsy include severe pain, organ perforation, and bleeding.28,29 This potential for complications has generated an increasing acceptance of alternative assessments of hepatic fibrosis, especially in patients with hepatitis C (Table 1). Unfortunately, for many such panels, availability, third-party payment, or widespread clinical consensus is lacking. Fibrosis related to chronic hepatitis C progresses slowly (on average 0.15 stages per year30), and a feasible alternative to liver biopsy must be able to measure this progression over time. Evaluations using standard laboratory tests, including the aspartate aminotransferase/alanine aminotransferase ratio, the cirrhosis discriminant score, the age-platelet index, the Pohl score, the aspartate aminotransferase to platelet ratio index, and platelet counts, lack either the sensitivity or the specificity needed to be useful in clinical practice.31,34,35 In addition, these noninvasive fibrosis markers may have reduced performance in hepatitis C patients with normal alanine aminotransferase levels.36 Larger test panels, including Hepascore, Liverscore, and FibroTest, have high potential for false-positive results and are not readily available in clinical practice.32,37-39 These laboratory tests and panels have not reliably detected intermediate stages of fibrosis or the progression of fibrosis, and this is valuable information for clinical decision making.30,40 Transient elastography produces suboptimal results in obese patients and in tracking changes in fibrosis.41-43 The reproducibility of transient elastography is significantly reduced (P < 0.05) in patients with steatosis, an increased body mass index, or lower degrees of hepatic fibrosis.

Table 1. Noninvasive Markers for Liver Histological Assessments (Including Tests for Fibrosis, Necroinflammation, and Steatosis)

Test	Components	Sensitivity/Specificity for Advanced Fibrosis (%/%)
The data for this table were taken from Rockey and Bissell,30 Lackner et al.,31 Adams et al.,32 Sanai and Keeffe,33 and Sebastiani et al.36 Abbreviations: A2M, alpha-2-macroglobulin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; HA, hyaluronic acid; INR, international normalized ratio; PIIINP, amino-terminal propeptide of type III collagen; TIMP1, tissue inhibitor of metalloproteinase 1.
FibroTest-ActiTest	Age, sex, A2M, GGT, haptoglobin, total bilirubin, apolipoprotein A1, ALT	87/59
FIBROSpect II	HA, TIMP1, A2M	83/66
European Liver Fibrosis Group algorithm	Age, PIIINP, HA, TIMP1	90/41
FibroMeter	Age, sex, A2M, HA, platelet count, AST, prothrombin	82/−
Hepascore	Age, sex, HA, A2M, GGT	67/92
AST-to-platelet ratio index	AST, platelet count	41/95
AST/ALT ratio	AST, ALT	53/100
Forns index	Age, platelet count, GGT, cholesterol	94/51
Pohl score	AST, ALT, platelets	18/98
Age-platelet index	Age, platelet count	68/55
Cirrhosis discriminant score	AST, ALT, platelet count, INR	10/100
Fibrosis prediction index	Age, AST, cholesterol, past alcohol use, insulin resistance	85/48
FibroScan	Hepatic transient elastography	64/87
FIB-4	Age, AST, ALT, platelet count	71/65

Percutaneous liver biopsy is considered the gold standard for histology assessment, yet it has a widely recognized sampling error rate as high as 20% for the detection of encircling fibrotic nodules with the evaluation of just 1/50,000 of the total organ.44 Such samples can be useful only if there are an adequate number of complete portal tracts, and with a length of 2 cm and a width of 1.4 mm, this goal is often not achieved in clinical practice. Moreover, the discordance between biopsy samples taken from right and left lobes further demonstrates the inherent limitations of this time-honored diagnostic test.44,47 Despite these challenges, a liver biopsy sample from a patient with hepatitis C in the new antiviral era remains a source of invaluable information. This information can be combined with available clinical and laboratory evidence (often surrogate markers with their own inherent limitations) to best serve the patient. A physician's or patient's reluctance to undertake the risks of biopsy should not represent a contraindication to antiviral therapy but rather should serve as the basis for a discussion of our limitations in assessing liver function and disease severity.

References

Source

Management of adverse events during the treatment of chronic hepatitis C infection

Clinical Liver Disease

Volume 1, Issue 2, pages 54–57, April 2012

Douglas L. Nguyen M.D.¹, Timothy R. Morgan M.D.^2,*

Article first published online: 26 APR 2012

DOI: 10.1002/cld.33

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

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DRESS, drug reaction with eosinophilia and systemic symptoms; ESA, erythropoietin-stimulating agent; FDA, Food and Drug Administration; PEG-IFN, peginterferon; RBV, ribavirin; SJS, Stevens-Johnson syndrome; SSRI, selective serotonin reuptake inhibitor.

Adverse events (side effects) are commonly observed in patients undergoing treatment for chronic hepatitis C (Table 1). Treatment with telaprevir and boceprevir can worsen side effects frequently associated with peginterferon (PEG-IFN) and ribavirin (RBV) treatment and can cause different adverse events. This overview focuses on the management of common adverse events that are associated with protease inhibitor treatment (Table 2).

Table 1. Commonly Encountered Side Effects During the Treatment of Chronic Hepatitis C

• Hematological
• Anemia
• Neutropenia
• Thrombocytopenia
• Neuropsychiatric
• Difficulty with concentration
• Depression
• Insomnia
• Irritability
• Dermatological
• Alopecia
• Localized skin irritation at the PEG-IFN injection site
• Erythematous maculopapular eruptions
• DRESS
• SJS
• Other
• Flu-like symptoms
• Fatigue
• Generalized achiness
• Thyroid disorders
• Dysgeusia
• Anorectal discomfort
• Diarrhea
• Hyperuricemia

 

Table 2. Management Strategies for Common Side Effects

*Trazodone and zolpidem have drug interactions with boceprevir and telaprevir and initially should be used at low doses.
Flu-like symptoms	Rest, fluid intake, and antipyretics (i.e., acetaminophen and nonsteroidal anti-inflammatory drugs)
Fatigue	Rest and psychostimulants, ondansetron, or dopamine agonists
Dyspnea	RBV dose reduction
Generalized aches	Serotonin-norepinephrine reuptake inhibitor (i.e., duloxetine)
Depression	1. SSRIs (e.g., citalopram)
	2. Psychiatric referral for refractory depression or suicidal ideation
Insomnia	Trazodone or non-benzodiazepine hypnotics*
Alopecia	1. Hats and head coverings
	2. Reassurance that hair will regrow after the discontinuation of therapy
Anemia	1. RBV dose reduction
	2. ESAs (not FDA-approved for this indication)
	3. Discontinuation of protease inhibitors if anemia is refractory to RBV dose reduction and ESAs
Hyperuricemia	Allopurinol if the serum uric acid level is >9.5-10 mg/dL

Before Starting Treatment

It is important for providers to anticipate, recognize, and respond to side effects in order to achieve compliance with therapy. Patient education before treatment should include a full discussion of potential side effects. Patients should be instructed to call the physician's office if they experience significant side effects.

Symptomatic Adverse Events

Flu-Like Symptoms

The most common side effects associated with PEG-IFN therapy are flu-like symptoms, which include fever, headache, myalgias, general aches and pains, sweating, chills, and nausea. These symptoms occur shortly after the first injection and often decrease during the course of treatment. Management is symptomatic, with reassurance, rest, oral fluid intake, and nonsteroidal analgesics used as needed. For generalized aches and pains, a serotonin-norepinephrine reuptake inhibitor (i.e., duloxetine) can be considered.1 More than half of the patients undergoing treatment with triple therapy report fatigue.2-4 Psychostimulants (methylphenidate and dextroamphetamine), odansetron,5 and dopamine agonists6 may alleviate fatigue but are not commonly prescribed.

Neuropsychiatric Effects

In phase 3 trials, approximately 15% to 25% of patients receiving PEG-IFN, RBV, and a protease inhibitor suffered from depression.3,4 Symptoms that should be treated as depression equivalents include irritability, anger, insomnia, and easy crying. The use of a standardized questionnaire (e.g., the Beck Depression Inventory, the Center for Epidemiologic Studies Depression Scale or the Major Depression Inventory) may detect more patients with depression than routine clinical examinations.7, 8

Mild to moderate depression can be managed by the hepatitis C specialist with the use of selective serotonin reuptake inhibitors (SSRIs).9 Among patients with preexisting depression or anxiety, pretreatment with an antidepressant can significantly reduce aggravating depression and anxiety during the treatment course.10,11 Insomnia can be treated with SSRIs, non-benzodiazepine hypnotics, or trazodone.

A comprehensive and multidisciplinary mental health program improves adherence to hepatitis C virus therapy.12 Patients with significant depression despite SSRI treatment should be referred for psychiatric consultation. Patients with suicidal ideation should stop treatment and/or be followed closely by a psychiatrist.

Dermatological Effects

Approximately 50% of patients treated with telaprevir develop cutaneous reactions, with most rashes occurring during the first 4 weeks of treatment.13-15 Although most skin reactions are mild to moderate, approximately 5% to 6% may be severe enough to require the discontinuation of telaprevir (and possibly PEG-IFN and RBV) (Table 3).13-15 It is not possible to predict which patients will develop progressive skin reactions; occasionally, skin reactions progress quickly.

The rashes are erythematous, maculopapular eruptions (morbiliform drug eruptions) that typically occur on the torso, arms, and head, but they can also occur on the legs. Patients should be assessed every 1 to 2 weeks to determine whether there is an increased percentage of skin involved or an increase in erythema or induration.

 

Table 3. Management of Telaprevir-Associated Rashes

Mild to moderate rash	This type of rash is erythematous and macular. It is usually found on the torso, arms, and head and involves less than 50% of the body surface area. Eosinophilia is often present.	1. Monitor every 1-2 weeks for the progression of the rash (a greater extent or greater erythema or induration) or the development of systemic symptoms.
		2. Use oral antihistamines (nonsedating or sedating) as needed:
		Cetirizine (5-10 mg daily)
		Fexofenadine (60-180 mg daily)
		Loratadine (5-10 mg daily)
		Diphenhydramine (12.5-25 mg 4 times daily)
		Hydroxyzine (10-25 mg 4 times daily)
		3. Apply topical corticosteroids to pruritic areas (but not the face):
		Triamcinolone (0.1% twice daily)
		Fluocinonide (0.05% twice daily)
		Hydrocortisone [2.5% with 1% pramoxine in a hydrophilic lotion (Pramosone)]
Severe rash	This type of rash involves more than 50% of the body surface area. Eosinophilia is usually present.	1. Discontinue telaprevir.
		2. Continue PEG-IFN and RBV.
		3. If there is no improvement in the rash after 7 days, discontinue PEG-IFN and RBV.
		4. Monitor weekly until the rash is resolved
		5. Consider a dermatological consultation.
Serious skin reactions (DRESS or SJS)	There are systemic symptoms such as fatigue. Eosinophilia (DRESS) is present. Alanine aminotransferase levels are often increased. There are mucous membrane ulcerations (SJS) and bullae.	1. Discontinue telaprevir, RBV, and PEG-IFN.
		2. A dermatological consultation is strongly recommended.
		3. Do not use oral steroids to treat the rash.
		4. Monitor weekly until the rash is resolved.
Skin care tips		1. Apply moisturizers at least twice daily.
		2. Use mild, unscented soaps and take warm (not hot) showers.
		3. Limit sun exposure.

General skin care includes the use of non–alcohol-containing skin moisturizers at least twice daily, the limitation of sun exposure, the use of mild, unscented soaps, and the avoidance of hot showers. Mild to moderate rashes can be managed with topical steroids and oral antihistamines; oral steroids are not recommended as a treatment for rashes. Rashes involving more than 50% of the body surface area, especially when there are worsening generalized symptoms (e.g., more fatigue) or increases in alanine aminotransferase or aspartate aminotransferase levels, suggest a serious drug reaction requiring the discontinuation of telaprevir. Patients should be evaluated 1 week after the discontinuation of telaprevir to ensure that the rashes have stabilized or improved. If the rashes progress despite the discontinuation of telaprevir, then PEG-IFN and RBV should be stopped. Significant skin reactions may take 4 to 6 weeks to completely resolve.

Severe rashes [e.g., Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS)] have been reported in less than 1% of patients receiving telaprevir. The US Food and Drug Administration (FDA) recommends the immediate discontinuation of all three drugs if serious skin reactions occur (i.e., SJS or DRESS).13 Consultation with a dermatologist is strongly recommended.

Other Symptoms

The addition of boceprevir and telaprevir to PEG-IFN/RBV results in a higher incidence of dysgeusia, nausea, vomiting, and diarrhea in comparison with PEG-IFN/RBV alone.4,14,15 These symptoms are usually mild and rarely require the discontinuation of the protease inhibitor. Bowel movements can be controlled with loperamide or diphenoxylate and atropine.

 

Table 4. Management of Anorectal Discomfort

Topical steroids (low potency)	1% hydrocortisone cream or ointment (may cause skin atrophy if it is used for more than 2 weeks and can be alternated with petrolatum jelly)
	Hydrocortisone acetate suppositories (e.g., Anucort-HC)
Topical local anesthetics	1% hydrocortisone/1% pramoxine foam (Proctofoam-HC)
	Lidocaine jelly
Nocturnal itching	Diphenhydramine
	Loratadine
Diarrhea	Fiber supplementation
	Loperamide
	Diphenoxylate and atropine

Up to 25% of patients receiving telaprevir complain of anal/perirectal symptoms, which have been described as discomfort, burning, itching, and/or hemorrhoids.13-15 Treatment is symptomatic and includes careful cleaning (with wet toilet paper or commercial products such as hemorrhoidal wipes) followed by a topical hydrocortisone cream (1%-2.5%) (Table 4). Hydrocortisone acetate suppositories (e.g., Anusol-HC), Proctofoam-HC, and lidocaine jelly have also been used.16-18

Laboratory Adverse Events

Hematological Events

In patients receiving PEG-IFN/RBV, the hemoglobin level decreases approximately 3 g/dL during the first 12 weeks of therapy19,20; 9% to 16% of patients have a hemoglobin nadir less than 10 g/dL.21-23 The addition of boceprevir or telaprevir to PEG-IFN/RBV leads to an additional decrease in the hemoglobin level of approximately 1 g/dL beyond that observed with PEG-IFN/RBV alone.4,13-15,23 A hemoglobin nadir less than 10 g/dL occurred in 52% of patients receiving boceprevir and PEG-IFN/RBV4 and in 37% of patients receiving telaprevir and PEG-IFN/RBV.13 It is important to note that the use of erythropoietin-stimulating agents (ESAs) was permitted for the treatment of anemia in phase 3 trials of boceprevir but not in phase 3 trials of telaprevir.

Neutropenia and thrombocytopenia are also common side effects of PEG-IFN.24-26 Despite the reduction in the absolute neutrophil count, the rate of bacterial sepsis is low and does not appear to correlate with the duration or nadir of neutropenia in PEG-IFN/RBV–treated patients.24,25 Telaprevir and boceprevir have been associated with neutropenia and thrombocytopenia beyond that seen with PEG-IFN/RBV alone,4,27 presumably because of bone marrow suppression.

The primary management of hematological side effects during treatment for hepatitis C, as recommended in the package inserts, is the reduction of the dose of PEG-IFN or RBV.13,27 Reducing the dose of RBV, even below 60% of the cumulative dose, does not appear to reduce the sustained viral response as long as RBV is not interrupted for more than 7 consecutive days.28,29 Post hoc analyses suggest that an RBV dose reduction for anemia does not reduce the sustained viral response among patients receiving boceprevir or telaprevir.4,13,27

Although ESAs are not approved by the FDA for the treatment of anemia among patients undergoing hepatitis C treatment, this strategy is employed in clinical practice.4,28-30 The FDA has given ESAs black-box warnings for increased risks of thrombosis, stroke, cancer (among patients with prior cancer), and pure red cell aplasia.30 Our clinical practice is to use ESAs only if an RBV dose reduction is ineffective. ESAs should be reduced when the hemoglobin level is greater than 10 g/dL and stopped before the hemoglobin level reaches 12 g/dL. If dose reductions of RBV and the administration of erythropoietin are inadequate, consider the discontinuation of the protease inhibitor.13,27

The dose of PEG-IFN should be reduced when the absolute neutrophil count is less than 750/μL and stopped when it is less than 500/μL; a minority of hepatologists continue to use low doses of PEG-IFN despite a neutrophil count less than 500/μL. A small clinical trial has demonstrated that filgrastim can be used to stimulate neutrophil production in patients receiving interferon.31 Eltrombopag, a thrombopoietin agonist, can increase the platelet count in patients with cirrhosis and thrombocytopenia.32 However, eltrombopag is associated with an increased risk of portal vein thrombosis in patients with chronic liver disease33 and should be used only with close monitoring and full disclosure to patients.

Other Laboratory Abnormalities

Telaprevir is associated with an elevation of serum uric acid, which begins during the first few weeks and continues as long as telaprevir is being used.13 Allopurinol should be considered when the serum uric acid level exceeds 9.5 to 10 mg/dL. A typical regimen is 100 mg of allopurinol daily for the first week and 100 mg twice a day thereafter.

References

Source

Importance of patient education and monitoring among HCV-infected patients selected for anti-viral treatment

Clinical Liver Disease

Volume 1, Issue 2, pages 41–45, April 2012

Review

Corinne Wentworth-Kotara^*, P.A-C.

Article first published online: 26 APR 2012

DOI: 10.1002/cld.9

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

Watch the interview with the authors

Answer questions and earn CME

HCV, hepatitis C virus; INO, independent nonprofit organization; PAP, patient assistance program; PCR, polymerase chain reaction.

The recent introduction of direct-acting antiviral agents to the armamentarium for treating patients chronically infected with hepatitis C virus (HCV) genotype 1 has improved the efficacy of antiviral treatment,1-3 but it also presents new challenges. As advanced and complex therapies evolve, ancillary staff will have to overcome a steep learning curve to ensure that patients are appropriately managed and successfully complete their treatment.

The selection of candidates for treatment is critical. The documentation of a patient's previous experience with interferon-based therapy, including dose reductions, side effects, and responses (null response, partial response, or relapse), is important in planning the treatment and estimating the chance of a response. Potential drug-drug interactions must be addressed; this may require changing or discontinuing some medications. These issues are described in other articles of this issue of Clinical Liver Disease.

This article presents practical guidelines for implementing antiviral treatment and monitoring patients throughout the course of the treatment. Triple-drug therapy is expensive and labor-intensive for both the provider and the patient. Considerable time and effort can be saved by the development of standardized protocols and flow sheets, familiarity with the drug approval process, patient education, and patient support services. Although these issues may seem mundane and require a considerable investment of time, they ultimately provide the most efficient way of administering therapy and optimizing outcomes.

Prescribing Information

Selection of a Pharmacy

Most prescriptions for HCV therapy now require the use of specialty pharmacies. Although the patient's insurance may require a specific pharmacy, knowing what services are provided by the specialty pharmacies in your area can save you considerable work. For example, some handle the prior authorization process, whereas others defer this time-consuming process to the provider. Others offer patient education services and 24-7 phone support. All should notify you about drug shipments, potential disruptions in shipment schedules, and patient calls. The initial drug shipment should not occur before the patient has been instructed in dose timing, side-effect management, and so forth (discussed later). Finally, ensure that the pharmacy is able to refill the prescription for the entire treatment course; beware of the one-time fill situation in which the insurance company requires a different pharmacy to provide the refills. This can disrupt the continuity of care if there is a delay in transferring the prescription or reauthorization is required.

Prior Authorization

Patients must have adequate funding to afford the medications and the required monitoring during treatment. Commercial and government health insurance generally covers at least part of this cost, although coverage and copays vary widely. The process of prior authorization differs among carriers and can be straightforward or painfully complex. At a minimum, it requires demographic information, recent laboratory results (including the viral load and genotype), clinical notes, and documentation that the patient does not have an absolute contraindication to therapy.

Co-Pays, Patient Assistance Programs (PAPs), and Independent Nonprofit Organizations (INOs)

Specialty pharmacies that assist with prior authorization generally communicate information about copays to patients before they dispense medications; otherwise, this falls to the provider. Copays may differ for each of the drugs and may vary from nothing to more than half of the cost. For patients unable to afford the copays, assistance is available, but it may not be sufficient to cover the difference. Unfortunately, those with Medicare, Medicaid, and other forms of government insurance (e.g., residents of Massachusetts) are excluded from these programs. These programs are listed in Table 1. Patients with commercial insurance who have large out-of-pocket expenses may be referred to a third-party copay assistance program. These INOs sometimes offer grants to patients, and these grants vary in amount and duration. Manufacturers and PAPs can refer patients to INOs but cannot influence or control INOs or guarantee copay assistance. It is important to understand the difference between the programs and the assistance that they offer. INOs are reviewed in Table 2.

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Table 1: Industry-Sponsored PAPs

Genentech

Pegasys
Pegasys Access Solutions4
888-941-3331 888-941-3331 http://www.genentechaccesssolutions.com
The company refers patients to INOs for copay assistance programs and assists with the application process.

Copegus
Genentech Access to Care Foundation
1 DNA Way, Mail Stop 858a, South San Francisco, CA 94080-4990 888-941-3331 888-941-3334 (fax)
The company provides free medicine for up to 1 year to uninsured patients, patients denied by health care plans, and patients not covered by Medicare or Medicaid. The adjusted gross income must be <$100,000. Patients must meet medical criteria. The company does not cover the costs of monitoring or office visits.

Kadmon

Ribasphere Ribapak
Aspire5
1640 Century Center Parkway, Department 053, Memphis, TN 38134 888-668-3393 800-724-8036 (fax)
Patients have no insurance and meet undisclosed program guidelines.

Merck

1. Peg-Intron
2. Rebetol
3. Victrelis

ACT Program6
833-363-6379  http://www.merck.com/merckhelps/act-program/home.html
The company provides free reimbursement support services related to insurance issues and refers patients to the PAP for free medication if they are eligible.

1. Peg-Intron
2. Victrelis

Merck Cares7
http://www.merck-cares.comhttp://www.victrelis.com
A copay assistance card covers up to $200 per fill for 12 fills. The encompassing site includes access to education, resources, and support for patients.

Vertex

Incivek
Guidance and Patient Support8
855-837-8394 http://www.incivek.com/vertex-guidance-patient-support
There is no income requirement. The company covers 20% (up to $10,000) of any type of out-of-pocket expense.

Patients are required to disclose their annual income (typically Internal Revenue Service form 1040) and the number of household members; each program has specific financial coverage and requires certification that patients are treatment-appropriate candidates. Patients also must be US residents without Medicare, Medicaid, or other federal government insurance coverage (e.g., Tricare or Champus). Patients residing in Massachusetts are excluded from participation.

Table 2: INOs That May Provide Grants for Drug Support

Patient Access Network Foundation9
P.O. Box 221858, Charlotte, NC 28222-1858 866-316-7263 http://www.panfoundation.org
There is an online application. Insurance is required. Income must be below the federal poverty level. Patients must reside and receive treatment in the United States.

Patient Advocate Foundation: Co-Pay Relief Program10
421 Butler Farm Road, Hampton, VA 23666 866-512-3861 http://www.patientadvocate.org
There is an online application. Direct financial support is provided to insured patients, including Medicare Part D beneficiaries who qualify. Patients are helped on a first-come, first-serve basis.

Chronic Disease Fund11
6900 North Dallas Parkway, Suite 200, Plano, TX 75024 877-968-7233 http://www.cdfund.org
This program is for privately insured patients and Medicare Part D patients unable to afford medication. There are three programs (public, private foundation, and PAP). An online application is available. Only Pegasys and Peg-Intron are covered.

INOs operate independently. Qualifications and awards are specific to INOs and are not influenced or controlled by manufacturers of specific HCV medications.

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Getting Started

Patient Education

Patient education is essential to the success of therapy. Structured one-on-one or group sessions work best and should be conducted immediately before therapy is begun. The key points of this discussion are listed in Table 3. Because this education is extensive, it should be considered a billable event, and a bill for appropriate reimbursement should be submitted to the insurance company (Current Procedural Terminology code 99215). Patients must be instructed not to start oral therapy before pegylated interferon is initiated because of the risk of drug resistance.

Table 3. Pretreatment Patient Education

Talking Point	Specifics	Key Points
Disease	Simple explanation of HCV	The virus is like other viruses but lives in and can damage the liver.
		The virus level does not influence disease severity.
		The virus level is important only for the treatment response.
		The virus can be eradicated; this is the goal of treatment.
	Liver disease	The course is usually slow (over decades), but it is different in everyone.
		Inflammation leads to scar tissue.
		Scarring may lead to cirrhosis.
		Cirrhosis can lead to complications.
		The goal is to avoid cirrhosis.
Treatment background	Pegylated interferon	The drug stimulates the body's defense system against viruses.
		Review potential side effects.
	Ribavirin	Unknown mechanism.
		Review potential side effects.
	Direct-acting antivirals for genotype 1	They interfere with the virus machinery.
		Review potential side effects.
		They do not work without the other drugs!
Goal of treatment	Definition of endpoints	Permanent eradication of the virus (viral cure).
		This does not negate the need for subsequent follow-up of liver disease.
Drug-drug interactions	Patient's medications	Absolutely contraindicated drugs.
		Relatively contraindicated drugs
		Need for dose adjustments or changes in medications.
		Notify the provider of any new medications before starting them.
Contraception	Potential teratogenicity	Potential for reduced effect of oral contraception.
		Alternatives: spermicide/condoms, intrauterine device, and diaphragm.
Adherence to therapy	Adherence is critical.	Take medications on time (every 8 hours and not just 3 times daily).
		Do not change doses or hold doses without instructions.
		Do not interrupt any medication (P/R/DDA).
Treatment initiation	Order of doses	Pegylated interferon is always first.
		Start ribavirin and telaprevir after the interferon dose.
		Pegylated interferon/ribavirin lead-in with boceprevir.
Therapy monitoring	Weekly and monthly labs	It is important to identify drug toxicity and treatment responses.
		Missing a week 4 viral load prohibits truncation of therapy.
Side-effect management	Anemia	Ribavirin dose reduction, erythropoiesis stimulating agents, and blood transfusions
	Rash	Topical antihistamines or topical steroids. Dermatology consult.
		Stop for severe rash (vesicle or bullae), drug reaction with eosinophilia and systemic symptoms, or Stevens-Johnson syndrome.
		Consider a dermatology consult if the rash is severe.
	Anorectal events	Over-the-counter hemorrhoidal preparations.
		3% topical lidocaine.
		There may be improvement with an increased amount of fat in the diet.
	Provider's ability to manage these events	Who to call on weekends and evenings.

Drug-Drug Interactions

Drug-drug interaction can influence the safety, tolerance, and effectiveness of therapy. This is discussed in detail in another article in this journal. The patient's medication list should be reviewed at each visit, and the patient should be instructed to check with you before any new medications, including over-the-counter and herbal preparations, are started.

On-Treatment Monitoring

Laboratory testing must follow a predefined schedule in order to appropriately modify the treatment duration, address adverse events, and discontinue treatment when it becomes futile. Viral load evaluation time points are critical in determining eligibility for truncating therapy, and the results are sometimes required by the patient's insurer to continue therapy.

Because therapy is guided by viral levels, your laboratory should use a sensitive test (lower limit of detection = 10-15 IU/mL) and should provide results within a week. Thus, you may need to do some investigation to find out which assays are available from each laboratory and what their turn-around times will be. Although most tests (not all) currently available through reference laboratories are sensitive to this level, they are not all able to quantitate viral levels to this lower limit of detection. This is fine as long as one recognizes that “below the limit of quantification” does not mean that the virus is undetectable. The same assay should be used on each occasion, and this typically requires requesting the test by its specific laboratory code rather than simply requesting “HCV RNA, quantitative.” Assays and their accession numbers with the common reference labs are shown in Table 4.

Because the monitoring points, stopping rules, and treatment durations are complicated and differ with the drug being used and the patient's previous response, we find it helpful to use flow sheets that identify these critical time points and remind us about what action is indicated. These have proven to be invaluable for monitoring viral responses, cytopenia, and dose modifications.

Side-Effect Management

Side effects are discussed in detail in another article in this journal. The patient should recognize and report side effects as soon as possible so that early intervention can minimize their severity. Although most side effects develop gradually, anemia can sometimes develop rapidly and can be a challenge to manage. We find it helpful to measure the hemoglobin level more frequently, perhaps even weekly, if the patient is elderly or has renal dysfunction, preexisting anemia, or a history of anemia with a previous course of therapy. Ribavirin dose reduction is the first step and can often circumvent the need for growth factors, transfusions, or dose interruptions. Erythropoietin should be considered if the hemoglobin level falls quickly (erythropoietin is not Food and Drug Administration–approved for this indication).

Empowering the Patient to Ensure Successful Therapy

Finally, we find that enlisting the patient in the care team helps the patient to take a more active role in maintaining adherence to dosing and the monitoring schedule. This should start during pretreatment education and should be reinforced by including the patient in reviews of laboratory results (particularly viral levels) and by emphasizing the key points of the educational outline during clinic visits during treatment.

References

Source