August 15, 2013

Gilead Races against Competitors for an Oral Hepatitis C Cure

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By Todd Campbell - August 13, 2013 | Tickers: ABBV, GILD, MRK, VRTX | 0 Comments

Todd is a member of The Motley Fool Blog Network -- entries represent the personal opinion of the blogger and are not formally edited.

The search for a hepatitis C cure is one of the most active areas within biotechnology research and development.

One of the company's ushering in the next generation of hepatitis C treatment is Gilead Pharmaceuticals (NASDAQ: GILD). The company acquired hepatitis C drug sofosbuvir in its $11.2 billion acquisition of Pharmasset back in January 2012.

Sonosbuvir has a very good chance of beating rival drugs to the market. Those competing drugs are being developed by Vertex Pharmaceuticals (NASDAQ: VRTX), Merck (NYSE: MRK) and AbbVie (NYSE: ABBV), the drug manufacturing giant that split off from Abbott Labs last winter.

Gilead's hopes for first-to-market approval.

In April, Gilead reported strong Phase 3 trial data. Those positive results for sonosbuvir as a combination therapy with ribavirin for genotype 2 and 3 hepatitis C patients prompted Gilead to file for FDA approval. The filing also seeks approval for sonosbuvir combined with ribavirin and interferon for genotype 1 -- the most common variant of the disease. The FDA granted Gilead's application priority review in June.

However, the holy grail of Hepatitis C treatment is an interferon free oral treatment alternative.

Developing such a solution will likely grab significant share in the $20 billion hepatitis C treatment market because interferon comes with significant side effects and current non-oral treatments require injections, which many patients dread.

As a result of the opportunity, Gilead is studying 12 and 24 week dosing of oral sonosbuvir without interferon through its Ion 1 and Ion 2  trials.

If those trials work as hoped, doctors will likely make it a first line treatment, shifting use of current treatments from Vertex and Merck to second tier status. Vertex's Incivek - the fastest drug to reach one billion in sales after launching in May 2011 -- and Merck's Victrelis combined to generate $330 million in sales last quarter.

But, that underestimates the true potential for an oral hepatitis C treatment as many doctors are delaying treatment in hope of these new options. This suggests the first to market will see significant ramp in sales tied to pent-up demand.

Gilead's competitors aren't giving up.

That's not to say Vertex and Merck are giving up on the market. Both are committing significant resources developing their own interferon free choices.

Vertex hopes to follow up its highly successful Incivek with another all-oral option. However, the company's VX-135 faced headwinds in late July when the FDA put a partial hold on a mid stage trial of the drug due to toxicity concerns tied to the highest 400 mg dose. The trial is continuing for the lower 100 mg dose.

At Merck, the company announced its MK-5172 saw a 92% cure rate six months after completing a 12 week treatment course. MK-5172 was dosed alongside ribavirin in the trial.

But, the competitor closest to threatening Gilead in the race to launch is AbbVie. During an investment conference in July, the company suggested it could have the first oral drug approval. It is in the final stages of its phase 3 trials. If approved, AbbVie's drug would help the company diversify its sales away from mega-blockbuster Humira, which accounted for $2.6 billion in Abbvie sales last quarter, roughly 55% of the company's total revenue.

Despite pressure from AbbVie, Gilead seems to remain the front runner.

Its sonosbuvir treatment would require just one daily pill versus four for AbbVie's drug. And, sonosbuvir showed a 95% cure rate in Phase 2 trials, similar to AbbVie's cure rate following 12 weeks of treatment. This suggests even if AbbVie does get to market first, doctors and patients will likely favor Gilead's drug.

That could mean a big pay day for the company given there are roughly 180 million people infected with Hepatitis C worldwide. While drug development is notoriously difficult and setbacks do occur, it appears Gilead and AbbVie should be watched closely as either could see substantial revenue growth if granted approval, making them Fool-ishly attractive.

Source

NHS lifts ban on health workers with HIV

Published August 15, 2013 AFP

photo_1376569884507-1-HD

LONDON, England (AFP) –  The government said Thursday it would lift a ban on staff with HIV working in the state-run National Health Service from carrying out certain procedures on patients.

Staff who are undergoing treatment for HIV will be able to carry out all procedures from which they are currently banned, including surgery and dentistry, provided they are having effective anti-retroviral drug therapy.

England's chief medical officer, Professor Sally Davies, said there was no proof that anyone had contracted HIV from a health worker and it was time to scrap "outdated rules".

She said improved treatment meant HIV, the human immunodeficiency virus that can lead to AIDS, could often be managed and carriers could lead long and normal lives.

Self-testing kits for HIV will also be legalised in Britain from April 2014, to improve early detection of the disease.

"We've got outdated rules," said Davies.

"At the moment we bar totally safe healthcare workers who are on treatment with HIV from performing many surgical treatments, and that includes dentists."

She said: "What we want to do -- and want to get over -- is how society needs to move from thinking about HIV as positive or negative and thinking about HIV as a death sentence, to thinking about whether they're infectious or not infectious."

Davies said huge improvements in the treatment of HIV meant that today, carriers can lead "lives that are normal in quality and length".

"With effective treatment, they are not infectious," she added.

There are about 100,000 people with HIV in Britain although experts say a quarter of those who are infected do not know they have it.

In 2011, there were around 6,000 new diagnoses of HIV.

Apart from being on retroviral drugs, healthcare workers must also have an undetectable viral load of HIV, meaning the level of the virus in their blood is so low that the likelihood of transmitting it to another person is greatly reduced.

They will also have to be monitored every three months and sign a confidential register of infected staff.

There have been just four cases in Western countries of health workers infecting patients, with no cases ever recorded in Britain.

Deborah Jack, chief executive of the National Aids Trust (NAT), welcomed the new policy, which she said was "based on up-to-date scientific evidence and not on fear, stigma or outdated information".

Professor Damien Walmsley, scientific advisor to the British Dental Association, said the change brought Britain in line with many other countries.

"Dentists in the UK comply with rigorous infection control procedures to protect both patients and the dental team against the risk of transmission of blood-borne infections," he added.

Source

BMC Gastroenterology

Sanjeev Sockalingam, Alice Tseng, Pierre Giguere, David Wong

BMC Gastroenterol. 2013;13(86)

Abstract

Background Despite recent advances in hepatitis C (HCV) treatment, specifically the addition of direct acting antivirals (DAAs), pegylated interferon-alpha remains the backbone of HCV therapy. Therefore, the impact of DAAs on the management of co-morbid psychiatric illness and neuropsychiatric sequalae remains an ongoing concern during HCV therapy. This paper provides a review of the neuropsychiatric adverse effects of DAAs and drug-drug interactions (DDIs) between DAAs and psychiatric medications.

Methods We conducted a Pubmed search using relevant search terms and hand searched reference lists of related review articles. In addition, we searched abstracts for major hepatology conferences and contacted respective pharmaceutical companies for additional studies.

Results Limited data is available on the neuropsychiatric adverse effects of DAAs; however, data from major clinical trials suggest that DAAs have minimal neuropsychiatric risk. DAAs can potentially interact with a variety of psychotropic agents via cytochrome P450 and p-glycoprotein interactions. Triazolam, oral midazolam, St. John's Wort, carbamazepine and pimozide, are contraindicated with DAAs. DDIs between DAAs and antidepressants, anxiolytics, hypnotics, mood stabilizers, antipsychotics and treatments for opioid dependence are summarized.

Conclusions Although DAAs do not add significant neuropsychiatric risk, the potential for DDIs is high. Consideration of DDIs is paramount to improving medication adherence and mitigating adverse effects during HCV therapy.

Background

Treatment of hepatitis C virus (HCV), a virus infecting over 170 million worldwide,[1] has evolved over the last two decades and moved from interferon-alpha monotherapy to pegylated interferon-alpha (IFNα) in combination with ribavirin therapy. HCV therapy with IFNα and ribavirin has yielded overall sustained virological response (SVR) rates of approximately 54% to 56% with SVR rates for genotype 1 approximating 45% to 50%.[2,3] The next generation of HCV therapeutic agents is direct acting antivirals (DAAs) that still require the use of interferon-ribavirin combination therapy. Protease inhibitors, specifically telaprevir or boceprevir, in combination with IFNα and ribavirin (i.e. triple therapy) have improved SVR rates to 70% to 75% in HCV genotype 1 patients.[4,5]

Despite these enhanced SVR rates, psychiatric illness remains a barrier to widespread HCV treatment uptake due to the neuropsychiatric risks associated with IFNα. It is estimated that up to 50% of patients with untreated chronic HCV suffer from psychiatric illness when substance abuse and dependence is excluded.[6,7] Lifetime rates of mood, anxiety and personality disorders in untreated HCV-infected patients have each ranged from approximately 20% to 40%.[6,7] Treatment with pegylated interferon-alpha (IFNα) therapy can induce a myriad of neuropsychiatric side effects including depression in approximately 25% to 30% of patients undergoing IFNα therapy for HCV.[8–11] In addition, HCV-infected patients with pre-existing psychiatric disorders may experience an exacerbation of psychopathology secondary to IFNα.

Poorly managed psychiatric illness can lead to treatment discontinuation, poor adherence to treatment and serious psychiatric sequalae, such as suicide.[12,13] The onset of suicidal ideation and suicide on HCV therapy coincides with the onset of IFNα-induced depression (IFNα-D) and requires prompt recognition and treatment to prevent these serious psychiatric sequelae.[12,14] Integrated Hepatology-Psychiatric care models have demonstrated the capacity to mitigate neuropsychiatric risks associated with HCV therapy through improved access to psychiatric and psychological interventions.[15,16]

In the era of DAAs, adherence is paramount to treatment success given the strict dosing regimen of first generation HCV protease inhibitors (PIs). First generation DAAs have high pill burdens and frequent dosing intervals. Active depression has been associated with poor antiviral therapy (ART) in patients infected with human immunodeficiency virus (HIV).[17] Therefore, it is possible that poorly controlled psychiatric illness may compromise adherence to PI dosing schedules and as a result, reduce HCV treatment efficacy. Similar to the advent of HIV ART, first generation DAAs have also presented concerns regarding drug-drug interactions (DDIs) with medications including several psychotropic medications. Given the high prevalence of psychiatric illness in HCV-infected patients and need for psychotropic treatments for IFNα-induced neuropsychiatric side effects, an understanding of salient DDIs involving psychotropic medications is essential to the clinical care of patients treated for HCV.

With respect to DDIs, both boceprevir and telaprevir are substrates and inhibitors of CYP3A4.[18,19] Both agents also inhibit p-glycoprotein[18,19] and telaprevir may inhibit renal transporters.[20] Approximately 50% to 60% of available prescription medications are metabolized via CYP3A4 pathway.[21,22] Moreover, preliminary HCV data suggests that in clinical practice, 72% of patients had at least one DDI and 50% had at least two DDIs related to DAAs.[23] Therefore, there is a high potential for DDIs with HCV protease inhibitors, particularly if treatment for other comorbid conditions is necessary.

Interactions may be pharmacokinetic or pharmacodynamic in nature. Pharmacodynamic interactions impact drug efficacy or toxicity in an additive, synergistic or antagonistic manner. For instance, pegylated interferon and ribavirin have CNS effects that overlap with those of the antiretroviral regimens involving efavirenz; co-administration may theoretically contribute to adverse effects including depression, mood changes, and suicidality. Clinicians may therefore wish to avoid this combination if possible, particularly in patients with a history of significant mental illness.

Pharmacokinetic interactions may result in altered concentrations of one or more interacting drugs. Negative two-way interactions have been observed between both boceprevir and telaprevir and ritonavir-boosted HIV protease inhibitors, with significant reductions in exposures of HCV agents and HIV protease inhibitors; therefore, telaprevir should not be coadministered with ritonavir-boosted darunavir, fosamprenavir, or lopinavir[18] and boceprevir is not recommended for use with any boosted protease inhibitor.[24]

Negative consequences of drug interactions may include viral breakthrough and development of resistance, sub-optimal disease/symptom management, or drug toxicity and possible non-adherence.[25] These interactions highlight the challenges of managing multiple comorbidities in patients with HCV infection.

The purpose of this review was to evaluate the current evidence on: (i) the neuropsychiatric adverse effects of DAAs, and (ii) the DDIs between DAAs and psychotropic agents when used in HCV patients.

Methods

We performed a Pubmed search using MeSH headings "hepatitis C" AND "boceprevir" OR "telaprevir" combined with "mental disorders", "psychotropic drugs" and "drug interactions". We limited our search to English language studies published between 2000-April 2013. References for all review articles were searched for additional studies as well as conference abstracts. Additional information on psychiatric adverse effects and DDIs with DAAs were requested from Vertex and Merck. Due to the limited literature, data on psychiatric adverse effects was also obtained from registration trials for boceprevir and telaprevir. Theoretical drug interactions were included in the respective sections. Due to available data on antidepressant efficacy in depressed HCV populations, we discussed potential DAA and antidepressant DDIs in the context of clinical evidence for specific antidepressant agents for treating depression during HCV therapy. Level of evidence was derived from 2 recent guidelines and existing reviews[26–29] and a previously published grading system[30] was used classify evidence for only studies examining antidepressant treatment of depression during HCV therapy.

Results

Neuropsychiatric Side Effects of DAAs

Data on neuropsychiatric adverse effects of DAAs is limited and predominantly derived from landmark clinical trials for boceprevir and telaprevir (see Table 1).[4,5,31–34] Across trials, there was no significant difference in neuropsychiatric side effects between DAAs and treatment with peg- IFNα and ribavirin alone. It should be noted that the rates of neuropsychiatric sequalae from DAAs may be an underestimate, as patients with significant psychiatric illness were excluded from these studies and detection of psychiatric side effects did not utilize formal psycho-diagnostic tools. Only one study published data on anxiety during triple therapy and found a comparable reported rate of anxiety in patients treated with triple therapy (10%) versus standard therapy alone (12%).[4] Although studies focusing specifically on psychiatric complications of DAAs are lacking, this preliminary data suggests that DAAs confer a minimal risk of additional neuropsychiatric side effects.

Table 1.  Psychiatric adverse effects in DAAs

  Telaprevir trials Boceprevir trials
ADVANCE4 ILLUMINATE*31 REALIZE32 SPRINT-133 SPRINT-25 RESPOND-234
Psychiatric side effect            
Fatigue 57% (57%) 68% 55% (40%) 68% (55%) 53% (60%) 54% (50%)
Insomnia 32% (31%) 31% 26% (26%) 28% (38%) 33% (32%) 30% (20%)
Irritability 22% (18%) - 14% (16%) - 22% (24%) 19% (13%)
Depression 18% (22%) - 9% (14%) - 23% (22%) 12% (15%)
Anxiety 10% (12%) - - - - -

% - percent for study arm corresponding to current standard of care for DAA.

(%) – percent for pegylated IFNα and Ribavirin treatment arm.

*ILLUMINATE – did not have pegylated IFNα and Ribavirin treatment arm.

Antidepressant Use With DAAs

Antidepressants are used primarily in the treatment of depression and anxiety in both untreated HCV patients and patients undergoing IFNα therapy for HCV. Studies have explored the use of antidepressants in HCV as both prophylactic (i.e. antidepressant pre-treatment) and symptomatic treatment for IFNα-D. Two recent guidelines have specifically identified management of IFNα-D and provided recommendations for antidepressant therapy in HCV-infected patients (see Table 2). Based upon these guidelines and previous reviews,[26] only escitalopram currently has Level 1 evidence for treating or preventing depression emerging during HCV treatment.[35,36]

Table 2.  Evidence for antidepressant treatment of depression during HCV Therapy and drug interactions with DAAs

Level of evidence for depression treatment Antidepressant (route of metabolism) Known or potential interactions with DAAs Comments
Level 1 Escitalopram (CYP2C19, 3A4 >> 2D6) No interaction observed with boceprevir37 35% ↓ escitalopram AUC with telaprevir38 Boceprevir: no dose adjustment required. Telaprevir: May need to titrate escitalopram dose according to clinical response.
Level 2 Citalopram (CYP2C19, 3A4 >> 2D6) Potential for ↓ antidepressant concentrations based on escitalopram interaction data. Monitor and titrate dose according to clinical response.
Paroxetine* (CYP2D6) No interaction expected based on known pharmacologic characteristics. Monitor and titrate dose according to clinical response.
Level 4 Bupropion (CYP2B6), Fluoxetine (CYP2D6) No interaction expected based on known pharmacologic characteristics. Monitor and titrate dose according to clinical response.
  Sertraline (CYP2B6 > 2C9/19, 3A4, 2D6, UGT1A1 - possible), Mirtazapine (CYP2D6, 1A2, 3A4), Venlafaxine (CYP2D6 > CYP3A4) Potential for ↑ sertraline, mirtazapine, venlafaxine concentrations (clinical significance unknown). Use with caution; monitor and titrate dose according to clinical response.
  Desvenlafaxine (UGT>>3A4) [39,40] Potential for ↑ desvenlafaxine concentrations (clinical significance unknown). Monitor and titrate antidepressant dose according to clinical response.
  Tricyclic antidepressants i.e. Desipramine (CYP2D6>>UGT), Imipramine (CYP2D6, 1A2, 2C19, 3A > UGT), Trazodone** (CYP2D6> CYP3A) Potential increase in TCA concentrations resulting in dizziness, hypotension and syncope. Use with caution with DAAs, lower TCA doses are recommended.
  Nortriptyline (CYP2D6) No interaction expected based on known pharmacologic characteristics. Monitor and titrate dose according to clinical response.
Avoid (exceptional circumstances only) Duloxetine (CYP1A2, 2D6) Duloxetine: risk of hepatotoxicity. Duloxetine is contraindicated in liver disease.
Nefazodone (CYP3A4) Nefazodone: potential for ↑ nefazodone and/or DAA concentrations; also risk of hepatotoxicity. Nefazone was discontinued in the United States and Canada in 2003 due to hepatotoxicity concerns. Avoid use in liver disease.
  St. John's Wort (hypericum perforatum); induces CYP3A4 and P-gp.40 Potential for ↓ DAA concentrations. St. John's Wort is contraindicated with boceprevir19 and telaprevir.18

*Evidence in RCT for depressed mood component of major depression only.

**Trazodone is primarily used clinically for treating insomnia.

Level of Evidence: Level I (≥ 2 RCTs or meta-analysis), Level 2 (1 RCT), Level 4 (Case reports/series or expert opinion
).

Anxiety secondary to IFNα can also be treated with antidepressants, which are a first line treatment based upon the limited available literature (Level 4).[41,42] Escitalopram and citalopram may be beneficial options in treating anxiety disorders in HCV based upon the anecdotal reports of safety in HCV[43–45] and extrapolation of evidence from non-HCV anxiety treatment guidelines.[46] Clinicians should be aware of the potential risk of dose-related QT prolongation with citalopram and escitalopram.[47] The maximum recommended dose is citalopram 20 mg per day in patients with hepatic impairment, those 65 years of age or older, patients who are CYP2C19 poor metabolizers, or patients who are taking concomitant cimetidine or another CYP2C19 inhibitor.[48] In some countries, such as Canada, the maximum recommended dose for escitalopram in patients with hepatic impairment is 10 mg per day due to QT prolongation concerns.[49]

Drug interactions between DAAs and some antidepressants, specifically those affected by CYP 450 interactions of PIs, may lead to clinically significant adverse effects which impact tolerability to therapy for HCV. For example, SSRIs and Selective Noradrenergic Reuptake Inhibitors (SNRIs) can be associated with nausea, gastrointestinal upset, sweating and sexual dysfunction, which could emerge with PI related drug interactions.

Specific drug interactions with antidepressants and DAAs are summarized in Table 2. In a single study involving telaprevir, escitalopram area under the curve (AUC) was reduced by 35%, suggesting the need for clinicians to monitor the need for dose optimization on triple therapy.[50] No significant DDI has been observed between escitalopram and boceprevir.[37] Specific antidepressants, for example trazodone, that have a high sedative potential and potential for DDIs with DAAs can lead to increased sedation and may impact overall tolerability and compliance to both agents. Therefore, the selection of antidepressant agents during HCV therapy should include consideration of potential DDIs, in order to avoid possible adverse effects, which may negatively affect HCV antiviral treatment adherence. Clinicians should also be aware that St. John's Wort is a potent inducer of CYP3A4 and P-gp,[40] and is contraindicated with DAAs due to the potential risk for significant reductions in boceprevir or telaprevir concentrations.[18,19]

Benzodiazepine and Hypnotic Use With DAAs

Benzodiazepines may be a treatment option for anxiety symptoms in the context of HCV or secondary to IFNα; however, no large trials have examined the efficacy of anxiolytics in HCV.[16,41,42,51,52] Anecdotally, benzodiazepines have also been used short-term for insomnia in HCV-infected patients.[41] Furthermore, the prevalence of substance dependence in HCV patients has cautioned the use of benzodiazepines in this patient population. In general, short-acting benzodiazepines should be avoided due to potential rebound effect on anxiety and long-term benzodiazepine use may lead to tolerance and dependence.

If benzodiazepines are used, lorazepam, oxazepam or temazepam are preferred due to the reliance on glucuronidation, a process that is relatively preserved in patients with significant liver disease.[53] Furthermore, these three agents are the least susceptible to pharmacokinetic interactions with DAAs since they are not metabolized through the cytochrome P450 system. Most other benzodiazepine agents undergo metabolism solely or partially through CYP3A4, and thus concentrations may be increased by DAAs via CYP3A4 inhibition. Triazolam and oral midazolam are contraindicated with boceprevir and telaprevir, due to hypothesized or documented significant interactions. When administered orally, midazolam exposures were increased 430% in the presence of boceprevir[54] and almost 9-fold in the presence of telaprevir.[55] Intravenous midazolam concentrations increased 3.4-fold when co-administered with telaprevir.[55] Thus, while intravenous midazolam is not absolutely contraindicated with PIs, it is recommended that this combination be administered with caution in a setting which allows for close clinical monitoring for prolonged sedation and/or respiratory depression, and that dose adjustment of intravenous midazolam should be considered.[19]

Zolpidem is metabolized through a variety of CYP450 isozymes, including CYP3A, 2C9, 1A2, 2D6, and 2C19. In the presence of steady-state telaprevir, zolpidem exposures were unexpectedly reduced by 47%.[56] Close monitoring and dose titration of zolpidem is recommended if this agent is coadministered with telaprevir. Zopiclone is also metabolized predominantly by CYP3A4 and to a lesser degree by CYP2C8 and CYP2C9. Zopiclone concentrations may theoretically be increased by DAAs and require close monitoring. Most other benzodiazepines should be used cautiously in patients on DAAs. Clinicians may consider starting with a decreased benzodiazepine dose and monitoring for benzodiazepine-related toxicity, or selecting an alternate agent such as lorazepam, oxazepam or temazepam. Dose reductions are also recommended in patients with severe liver impairment as per product monographs.[18,19]

Anticonvulsant Use With DAAs

Anticonvulsants can be used as mood stabilizers for new onset or de-stabilized bipolar disorder during IFNα therapy for HCV. Studies on the efficacy of anticonvulsants as moodstabilizers in HCV are limited to case reports and as a result, treatment often follows non-HCV bipolar treatment guidelines.[30]

Lithium is a preferred moodstabilizer due its renal excretion and minimal dose adjustment in patients with HCV except in patients with shifting fluid balance resulting from decompensated cirrhosis.[57] Lithium has no known drug interactions with DAAs. Valproic acid has no significant DDIs with DAAs; however, valproic acid use in HCV has been limited by its purported risk of hepatotoxicity.[58] Nonetheless, in a study of patients with less severe HCV disease, elevations in alanine aminotransferase (ALT) were comparable between valproic acid and other psychotropic agents.[59]

Amongst the remaining moodstabilizers, carbamazepine is contraindicated due to induction of cytochrome P450 3A4 and potential for decreasing boceprevir or telaprevir levels (see Table 3). Lamotrigine undergoes extensive metabolism by UDP-glucuronosyltransferase (UGT) 1A4.[60] This metabolic pathway is not inhibited or induced by boceprevir or telaprevir. Lamotrigine has been associated with severe rash, including Steven's Johnson rash. Given that DAAs, particularly telaprevir, have also been associated with severe rashes, it is recommended to use extra precautions if coadministration is required. Gabapentin and pregabalin are not effective moodstabilizers for bipolar disorder in monotherapy;[61] however, based upon data from non-HCV populations pregabalin and gabapentin can be efficacious in treating co-morbid generalized anxiety disorder (GAD) in HCV. Both pregabalin and gabapentin have no significant drug interactions with HCV triple therapy involving DAAs as they are both predominantly renally excreted. Table 3 provides a summary of anticonvulsant drug interactions with DAAs.

Table 3.  Anticonvulsant drug interactions with DAAs

Drug (route of metabolism) Known or potential interactions with DAAs Comments
Lithium (renal) No interaction expected based on known pharmacologic characteristics Monitor and titrate dose according to clinical response and serum levels.
Valproic Acid, divalproex Parent: UGT (50%), minor CYP dependent oxidation pathway (<10%) Inhibitor of UGT,CYP2C9/19 No interaction expected based on known pharmacologic characteristics Monitor and titrate dose according to clinical response and serum levels.
Carbamazepine Parent: CYP3A>> 2C8, 1A2 Inducer of CYP3A, 2C9, 2C19, UGT and possibly 1A2 Potential for ↓ DAAs concentrations Carbamazepine is contraindicated with boceprevir19 Co-administration of telaprevir with potent CYP3A4 inducers such as carbamazepine may lead to reduced DAA plasma concentrations and decreased efficacy18 Carbamazepine clearance can also potentially be decreased.62 Consider an alternate agent with non-inducing metabolic properties.
Oxcarbazepine Parent: UGT Inhibitor of CYPC19; Potent inducer of CYP3A4. Relative to carbamazepine, oxcarbazepine inducing effect is 54% lower63 Potential for ↓ DAAs concentrations Co-administration of boceprevir and telaprevir with potent CYP3A4 inducers, may lead to reduced DAA plasma concentrations and decreased efficacy. Consider an alternate agent with non-inducing metabolic properties.64
Lamotrigine (UGT) No interaction expected based on known pharmacologic characteristics Monitor and titrate dose according to clinical response.
Gabapentin (Renal) No interaction expected based on known pharmacologic characteristics Monitor and titrate dose according to clinical response.
Pregabalin (Renal) No interaction expected based on known pharmacologic characteristics Monitor and titrate dose according to clinical response.

Antipsychotic Use With DAAs

Antipsychotic medications can be used during HCV therapy to stabilize pre-existing mood or psychotic disorders in patients or to treat IFNα-induced mood or psychotic symptoms secondary. Patients with severe mental illness, such as schizophrenia[65,66] and bipolar disorder[67] have been shown to have higher rates of HCV compared to the general population and thus, it may not be uncommon to treat patients with HCV who are already treated with antipsychotic medications for severe mental illness. Albeit rare, antipsychotic medications may be used to treat de novo secondary to IFNα.[68–72] In addition, atypical antipsychotics can be used for mood stabilization and irritability emerging during HCV therapy.[41,73,74]

Several DDIs and side effects should be considered when prescribing antipsychotic medication in the context of HCV triple therapy (see Table 4). Telaprevir and boceprevir may interact with antipsychotics prone to corrected QT (QTc) interval prolongation and elevations in plasma levels could increase QTc prolongation risk. As a result, pimozide, a conventional antipsychotic with a high propensity for QTc prolongation, is contraindicated when treating patients with boceprevir and telaprevir. Amongst the atypical antipsychotics, ziprasidone, which is metabolized by CYP 3A4, is associated with an increased QTc prolongation risk amongst novel antipsychotics.[75] Initiation of ziprasidone should include a baseline electrocardiogram (ECG) and this may need to be reassessed on triple therapy for HCV due to DDI.

Table 4.  Antipsychotic drug interactions with DAAs

Drug (route of metabolism) Known or potential interactions with DAAs Comments
Aripiprazole (CYP3A4, 2D6) Potential for ↑ aripiprazole concentrations Use combination with caution, and monitor for aripiprazole-related toxicity (sedation, sinus tachycardia, nausea/vomiting, or dystonic reactions). Consider starting with a decreased aripiprazole dose or select an alternate agent.
Asenapine (UGT1A4, CYP1A2) No interaction expected based on known pharmacologic characteristics Monitor and titrate dose according to clinical response.76
Clozapine (CYP1A2> 3A4,P-gp) Potential for ↑ clozapine concentrations Clozapine has a narrow therapeutic index. Use combination with caution, and monitor for clozapine-related toxicity (Bone marrow suppression, generalized seizures, severe sedation, confusion and delirium). Consider starting with a decreased clozapine dose or select an alternate agent. When available, clozapine therapeutic drug monitoring is recommended.77,78
Olanzapine (CYP1A2, UGT,PGP>2D6) No interaction expected based on known pharmacologic characteristics Monitor and titrate dose according to clinical response.
Paliperidone Primarily renally excreted (59%); minor CYP dependant pathway (CYP3A4, PGP>2D6), but may not be clinically significant. Substrate and inhibitor of P-gp79 Potential for ↑ paliperidone concentrations DAAs inhibit both CYP3A4 and P-gp, and clinically significant interaction, although unlikely, cannot be ruled out. Use combination with caution, and monitor for possible paliperidone-related toxicity.
Quetiapine (CYP3A4>2D6, P-gp) Potential for ↑ quetiapine concentrations Use combination with caution, and monitor for quetiapine-related toxicity (excessive sedation). Consider starting with a decreased quetiapine dose or select an alternate agent.80
Risperidone (CYP2D6, P-gp>3A4) Potential for ↑ risperidone concentrations Unlike its active metabolite paliperidone, risperidone is primarily metabolized by CYP2D6. However, the elimination of paliperidone may be impaired. Use combination with caution, and monitor for possible risperidone-related toxicity.
Ziprasidone (CYP3A4>1A2) Minor CYP dependant pathway (33%).78 Potential for ↑ ziprasidone concentrations Although clinically significant interaction unlikely, use combination with caution, and monitor for possible ziprasidone-related toxicity (QTc).

Several antipsychotics are metabolized via CYP3A4/5, which are inhibited by current DAAs. Sedating antipsychotics that are metabolized by CYP3A4, such as quetiapine, may be increased via DDIs secondary to DAAs and could result in more pronounced sedation that could hinder compliance with multiple daily dosing regimens of DAAs. Clozapine is also metabolized in part by CYP3A4 and clozapine levels should be monitored closely during HCV triple therapy as higher doses of clozapine have been associated with an increased adverse effects including seizures.[81] Treatment with clozapine is further complicated during HCV therapy due to additive theoretical risks of agranulocytosis and neutropenia related specifically to IFNα effects. Therefore, clozapine monitoring protocols may need to be adjusted due to this risk and vigilant follow-up monitoring for signs of infection is recommended.[82]

Lastly, DAAs are known inhibitors of P-gp and many second generation antipsychotics are substrates of P-gp.[83] In theory, inhibition of P-gp may lead to increased exposure of the antipsychotic in the CSF, and may be associated with enhanced effectiveness or toxicity.[79] Despite the absence of documented metabolic drug interactions, caution is to be exercised with known substrates of P-gp (quetiapine, risperidone, olanzapine) and DAAs.

Addictions Agents With DAAs

Given the higher rates of substance dependence in HCV-infected patient populations compared to the general population,[6] treatment of concurrent substance use disorders, either through harm reduction or abstinence based models, is an important component of pre-HCV therapy stabilization. To date, no studies have determined if the addition of DAAs to HCV treatment increased the risk of substance use relapse.

In some HCV-infected populations, methadone treatment is a core component of HCV treatment stabilization in patients at risk of opioid and polysubstance dependence.[84,85] Methadone is metabolized by CYP2C19 and 3A4. The coadministration of methadone and telaprevir was shown to result in a 21% decrease of the active enantiomer R-methadone exposure.[86] However, free concentrations of R-methadone were unaffected and therefore no dosage adjustment is necessary. Buprenorphine pharmacokinetics are not affected by telaprevir and is safe for coadministration.[87] Boceprevir was studied with methadone, buprenorphine and naloxone. Similar to telaprevir, boceprevir led to a 15% decrease of R-methadone exposure. No free methadone concentrations were performed. Boceprevir was also associated with an increase of naloxone and buprenorphine exposure by 19 and 33% respectively, which is considered to be clinically non-significant.[88]

Discussions

Psychiatric disorders are highly prevalent in patients infected with chronic HCV and until IFNα-free therapies for HCV emerge, it is evident that neuropsychiatric risks of HCV therapy continue to be a significant concern. This review provides further information on the impact of DAAs on the neuropsychiatric sequelae of HCV therapy and clarifies the potential for DDIs with psychotropic medications.

First, DAAs do not appear to confer additional neuropsychiatric risks to patients undergoing HCV triple therapy. However, the use of DAAs warrants careful recognition of potential DDIs with psychotropic agents and an analysis of whether psychotropic regimens should be changed due to significant DDI risks. In addition, the potential for DDIs with psychotropic agents may exacerbate side effects and may interfere with DAA compliance, thus reducing HCV treatment efficacy.

The potential for clinically significant and complex interactions between DAAs and psychotropic drug classes is high. Interactions are primarily pharmacokinetic in nature, and may result in increased or decreased exposures of either/both drug classes. Potential clinical consequences of such interactions may include increased toxicity or potential under dosing. In the case of DAAs, sub-therapeutic concentrations may lead to treatment failure and development of resistance. Whenever possible, non-essential medications should be discontinued for the duration of HCV treatment.

Steps to identifying and managing interactions include ensuring that medication records are up to date at each patient visit (i.e., medication reconciliation), use of a systematic approach to identify combinations of potential concern, consulting pertinent HCV drug interaction resources, and frequent patient monitoring. Other management options include altering dosing frequency or replacing one agent with another drug with lower interaction potential. Given the complexity of this field, clinicians are encouraged to consult with pharmacists or physicians with expertise in HCV pharmacology when managing drug therapy of co-infected patients.

The results of this review can be beneficial in informing the selection of psychotropic agents for common psychiatric presentations in HCV. Using self-report or clinician rated psychiatric scales to measure treatment response to pharmacotherapy can be beneficial in monitoring relapse following psychotropic dose adjustments due to DDIs. For example, both the Beck Depression Inventory-II[89] or Patient Health Questionnaire-9[87] for depression have been used and validated in this patient population. Further, awareness and education of the entire interdisciplinary treatment team is important in order to assist with prompt recognition of psychiatric symptoms, appropriate selection of psychotropic agents with minimal drug interactions and to minimize adverse effects to increased overall treatment adherence. The importance of interdisciplinary models of HCV care is evident from studies showing comparable HCV treatment adherence rates and outcomes for patients with either active substance use[84,90] or severe mental illness[91,92] as compared to controls.

Conclusions

In summary, this review summarizes the emerging body of evidence in this area but also acknowledges the remaining gaps in the literature. Studies utilizing more detailed psychiatric assessment tools during HCV treatment with DAAs are needed to increase our understanding of DAA related psychiatric complications. Additional drug interaction studies between DAAs and commonly used psychotropic agents are urgently needed. The results of these studies will be essential to guiding clinicians presented with challenges in interpreting DDI risks related to psychiatric care in the era of HCV triple therapy, in order to optimize HCV treatment outcomes and as well as management of psychiatric symptomatology.

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HCV SVR Improved Neurocognitive Function After SVR

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"We observed a significant improvement of neurocognitive function measured at least 1 year after the completion of a successful antiviral therapy. However, in nonresponders or in patients that relapsed after treatment with interferon/ribavirin, there was no significant change of performance in any of the TAP subtasks. From this, it can be concluded that the cognitive impairment in patients with active HCV infection is potentially reversible......we showed that within the subgroup of sustained responders (n = 116) the neurocognitive performance at the long-term follow-up evaluation was significantly improved in the TAP subtasks related to vigilance, divided attention [optical], and working memory compared to the baseline evaluation......In the group of patients who did not eliminate HCV (n = 52), the neurocognitive performance did not change significantly after termination of the antiviral treatment compared to measurements at baseline."

"......We suggest that the potential benefit of a successful therapy for chronic hepatitis C with respect to the patients' neurocognitive function should be considered as an additional treatment indication in this disease."

"Among the well-documented neurological and psychiatric side effects of interferon, an impairment of cognitive function by this drug during antiviral treatment for chronic hepatitis C has been well documented by us and others.[10, 11, 22] However, evidence from smaller studies suggests that the brain may be affected in patients with chronic HCV infection and noncirrhotic liver disease even before an antiviral treatment has been initiated.[23] These studies have mainly focused on cerebral magnetic resonance imaging (MRI) and functional single photon emission tomography (SPECT) neuroimaging in infected patients in comparison with healthy controls. From their results it remains unclear whether the hepatitis C virus per se has a direct effect on cerebral function, or whether the impairment is caused by the chronic inflammation in the liver."

Editorial

Cognitive improvement after HCV eradication: Extending the benefits

Hepatology August 2013

A direct effect of the hepatitis C virus (HCV) on the central nervous system (CNS) was proposed over 10 years ago as a mechanism for the neurocognitive impairment reported in this infection.[1] A number of studies have shown impairments in working memory, attention, executive function, and processing speed in patients with noncirrhotic HCV infection.[2] However, despite the many patients treated in the last decade, there have been no published studies on the effect of successful antiviral treatment on neurocognitive function in large prospectively studied cohorts. Over this period, α-interferon has remained the backbone of antiviral regimens and the CNS effects of this administered cytokine have been intensively studied during treatment.[3]

It is well established that α-interferon induces depressive symptoms in patients with HCV infection, which generally peak after 12 weeks of therapy. Other neuropsychiatric effects include fatigue, irritability, anxiety, and cognitive symptoms such as memory disturbances and concentration problems.[3] The underlying mechanisms of α-interferon-induced depression have been studied by researchers with an interest in the inflammatory hypothesis of depression and include alterations in the hypothalamic-pituitary-adrenal axis, perturbations in the metabolism of major neurotransmitters, and the activation of the enzyme indoleamine-2,3-dioxygenase (IDO), which leads to the degradation of tryptophan into neurotoxic pathways.[3] In parallel, predictors of α-interferon-induced depression have been sought and include genetic polymorphisms in the serotonin transporter and immune genes, blood levels of certain cytokines, e.g., interleukin-6, and other peripheral biomarkers such as docosahexaenoic acid.[3] However, there has been relatively little attention paid to the interaction between HCV-associated cognitive impairment and the on-treatment and delayed effects of α-interferon-containing therapy.

Fontana et al.[4] studied neurocognitive function in a cohort of patients with advanced fibrosis and cirrhosis who had previously failed to respond to pegylated α-interferon and ribavirin in the HALT-C study. When retreated for a prolonged period with low-dose maintenance pegylated α-interferon, they found no effect of treatment on cognitive function after up to 48 months. At baseline there was significant impairment in 28% of patients but no significant positive or negative effect of interferon was seen through treatment, raising the possibility that this group had minimal hepatic encephalopathy (MHE), which was unaffected by treatment. This study was not designed to evaluate the effect of viral eradication on neurocognitive function.

In contrast, in an earlier study[5] before the one published in this issue by Kraus et al.,[6] the same investigators reported a significant negative impact of α-interferon on vigilance, attention, and working memory in patients after 3-8 months of full-dose α-interferon-based treatment. There was a return to baseline cognitive function 6 weeks after the end of treatment but, again, the study was not designed to evaluate the effect of successful viral eradication. In contrast to the HALT-C cohort, this cohort had milder liver disease and the adverse effect of treatment was probably related to an absence of preexisting MHE and a higher dose of α-interferon.

In this issue, the same group now report significant improvement in neurocognitive function at least 12 months after the end of successful viral eradication with pegylated α-interferon-2b and ribavirin.[6] The group performed a series of tests evaluating executive function, including working memory and vigilance before and after therapy with a standard interferon and ribavirin regimen. The article is important in that it shows that in a "real-life" cohort of patients, there was improvement in cognitive function in patients who had a sustained virological response but not in those who failed to clear the infection. This suggests that, after the established adverse effects on interferon and ribavirin have receded, at least 12 months postcompletion of therapy an improvement in cognitive function attributable to viral eradication per se is evident. This reinforces the notion of a biological effect of HCV infection within the CNS. Although it is possible that knowledge of the treatment outcome might have affected cognitive performance in some way, it would not be feasible in a prospective study of this nature to blind patients to their treatment outcome for 12 months after the end of treatment.

The cohort that was studied had a relatively high sustained virological response rate and presumably did not include patients with multiple negative predictors of interferon response such as African Americans, obese individuals, and a high burden of advanced fibrosis. Although some patients with cirrhosis were studied, post-hoc analyses did not show this to be important in predicting cognitive dysfunction. This is important, as it suggests that preexisting MHE in cirrhosis nonresponders was not a confounding variable.

The finding of cognitive improvement that is independent of cirrhotic morphology is important because it adds impetus to further evaluating cognitive function as an indication for and as an outcome measure of antiviral therapy at a precirrhotic stage. Disentangling the relative contributions of HCV, cirrhosis, comorbid conditions, and concomitant medications can be challenging since available tests are sensitive but not specific.[7] MHE uniquely affects visuo-construction skills, motor speed, and motor accuracy, while precirrhosis HCV infection affects working memory and the domains of attention, executive function, and processing speed are affected in both.[8] The authors applied a relatively narrow battery of only four tests (alertness, divided attention, vigilance, and working memory), which were previously shown to be sensitive to the effect of interferon but are not specific to this or the effect of HCV infection itself. In this study, there was no comparison of baseline function with normative control data and the clinical significance of the improvement was not defined. Indeed, in future studies it will be important to link neurocognitive test performance with outcomes that affect daily life such as cognitive health-related quality of life, e.g., MOS-Cog, or Sickness Impact Profile, in order to increase acceptance of the effect on cognition as a valid outcome and as an added benefit of HCV therapy.

Despite increasing interest and research, there remains uncertainty around the mechanism of HCV-associated cognitive impairment and other CNS effects. Imaging studies have suggested evidence of CNS immune activation[1, 9, 10] and alterations in neurotransmission in HCV infection,[11] yet it is unclear whether this is associated with a direct effect of viral penetration into the CNS[12] or a result of peripheral factors acting across the blood-brain barrier. HCV genomes have isolated by a number of groups in human microglial cells[13] and recent data show that human brain endothelial cells support productive but low-level infection by HCV.[14] The potential importance of an extrahepatic, immune-privileged site goes beyond the neurocognitive symptoms in this infection, particularly as we move into the era of interferon-free, direct-acting antiviral therapy. The expected major improvements in sustained virological responses after finite short-course combination therapies will depend on adequate drug penetration to all sites.

The era of interferon-free regimens will greatly reduce the neurocognitive burden posed by interferon and offers further opportunities to test the relationships between HCV infection and CNS symptoms. In the absence of the deleterious effect of interferon, we should expect an accelerated improvement in neurocognitive symptoms if, as suggested, they are directly attributable to HCV per se and the promise of high-level, permanent viral eradication becomes reality.

Jasmohan S. Bajaj, M.D., M.Sc.1
Daniel M. Forton, Ph.D., FRCP2
1Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, and McGuire VA Medical Center, Richmond, VA 2Department of Gastroenterology and Hepatology, St George's University of London, London, UK

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Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C

Hepatology August 2013
Michael R. Kraus,1,2* Arne Schafer,1* Gerlinde Teuber,3 Heiner Porst,4 Kathrin Sprinzl,3 Sven Wollschlager,4
Christian Keicher,1 and Michael Scheurlen1

"We observed a significant improvement of neurocognitive function measured at least 1 year after the completion of a successful antiviral therapy. However, in nonresponders or in patients that relapsed after treatment with interferon/ribavirin, there was no significant change of performance in any of the TAP subtasks. From this, it can be concluded that the cognitive impairment in patients with active HCV infection is potentially reversible......we showed that within the subgroup of sustained responders (n = 116) the neurocognitive performance at the long-term follow-up evaluation was significantly improved in the TAP subtasks related to vigilance, divided attention [optical], and working memory compared to the baseline evaluation......In the group of patients who did not eliminate HCV (n = 52), the neurocognitive performance did not change significantly after termination of the antiviral treatment compared to measurements at baseline."

"......We suggest that the potential benefit of a successful therapy for chronic hepatitis C with respect to the patients' neurocognitive function should be considered as an additional treatment indication in this disease."

"Among the well-documented neurological and psychiatric side effects of interferon, an impairment of cognitive function by this drug during antiviral treatment for chronic hepatitis C has been well documented by us and others.[10, 11, 22] However, evidence from smaller studies suggests that the brain may be affected in patients with chronic HCV infection and noncirrhotic liver disease even before an antiviral treatment has been initiated.[23] These studies have mainly focused on cerebral magnetic resonance imaging (MRI) and functional single photon emission tomography (SPECT) neuroimaging in infected patients in comparison with healthy controls. From their results it remains unclear whether the hepatitis C virus per se has a direct effect on cerebral function, or whether the impairment is caused by the chronic inflammation in the liver."

Abstract

Earlier studies have suggested neurocognitive impairment in patients with chronic hepatitis C virus (HCV) infection even before liver cirrhosis has developed. Since these deficits might be reversible after successful antiviral therapy, we analyzed the long-term course of neurocognitive parameters in HCV patients with and without successful virus elimination by an interferon-based antiviral treatment. In a multicenter study including 168 HCV patients receiving antiviral therapy (peginterferon alpha-2b and ribavirin) we performed a long-term follow-up of neurocognitive performance before and after treatment.

Neurocognitive function was psychometrically assessed using the computer-aided TAP (Test Battery of Attentional Performance). When tested at least 12 months after termination of antiviral treatment, patients with sustained virologic response (SVR) had improved significantly as compared to their pretreatment performance in three of five TAP subtasks (vigilance, P < 0.001; shared attention: optical task, P < 0.001; working memory, P < 0.001). Patients who failed to eradicate the virus, however, showed no significant long-term changes in neurocognitive performance in all five subtasks assessed (0.194 < P < 0.804). In the posttreatment evaluation, neurocognitive function was significantly better in responders to the antiviral therapy as compared to nonresponders. Conclusion: Successful eradication of HCV leads to a significant improvement of relevant aspects of attentional and neurocognitive performance, indicating that the neurocognitive impairment caused by chronic HCV infection is potentially reversible. This therefore suggests an added therapeutic benefit of antiviral treatment in HCV infection. Improvement of neurocognitive function may be an additional treatment indication in patients with HCV.

An estimated 170 to 180 million people worldwide are chronically infected with the hepatitis C virus (HCV).[1, 2] Chronic hepatitis C may lead to progressive hepatic injury and eventually to liver cirrhosis and endstage liver disease.[3, 4] HCV infection is a leading cause of cirrhosis and hepatocellular carcinoma and a major indication for liver transplantation in the Western world.[4] The burden of chronic HCV infection remains substantial because of the high number of individuals infected before the identification of the virus.[8, 9] Until recently, the standard treatment for chronic HCV infection was peginterferon alpha combined with ribavirin administered for 24 (HCV genotype 2 or 3) or 48 weeks (genotype 1, representing the most prevalent genotype in North America and Europe). This treatment leads to a sustained virologic response (SVR) in ~50% of HCV patients.[9]

Impairments of attention, concentration, and memory are frequent complaints among hepatitis C patients, and an aggravation of these symptoms is reported during antiviral therapy with peginterferon alpha and ribavirin. A decline in neurocognitive function in these patients resulting from antiviral therapy has been described in the recent literature.[10, 11] However, little research has been performed to address the question of whether the chronic HCV infection and/or the concomitant hepatic inflammation per se lead to neurocognitive impairment, and whether such impairment may be reversible after successful interferon (IFN)/ribavirin therapy. The studies that have been published thus far are characterized by only small to moderate sample sizes and provide inconsistent results concerning the aspect of potential reversibility of morphological changes as documented by magnetic resonance spectroscopy.[12, 13] Therefore, we designed a longitudinal multicenter study to assess the long-term course of neurocognitive function in HCV patients treated with antiviral therapy, and to investigate the potential impact of SVR on neurocognitive performance.

Materials and Methods

Subjects

The participating patients were enrolled at three centers in Germany (Wurzburg, Frankfurt, and Dresden) between 2005 and 2008.

Eligible outpatients had to be between 18 and 65 years of age and to be chronically infected with HCV (as confirmed by the presence of HCV RNA detected by PCR [polymerase chain reaction: Cobas Amplicor] testing) with an indication for antiviral treatment. Previous unsuccessful therapy attempts with less effective treatment protocols (e.g., IFN monotherapy) were not an exclusion criterion. All participants were seronegative for hepatitis B surface (HBs) antigen and for human immunodeficiency virus (HIV; types 1 and 2). The absolute neutrophil count had to be above 1,000/μL, the platelet count above 90,000/μL, and the hemoglobin level within the normal range. Patients were excluded if they had decompensated liver disease, nonviral causes of clinically relevant liver disease, or hepatocellular carcinoma. A recent liver histology was not available for all patients because a biopsy was not a precondition for study participation. We treated our patients according to the current German guidelines for hepatitis C.[14] These guidelines preclude active alcohol intake during antiviral therapy. To guarantee the necessary degree of abstinence, patients who had consumed more than 40 g (males) or 20 g (females) daily were not included in the study.

The study protocol was approved by the Ethics Committees of the participating study centers and conformed to the ethical guidelines of the Declaration of Helsinki. All patients provided written informed consent for participation in the trial before enrolment.

Study Design and Organization

This was a longitudinal trial with a repeated-measures design (dependent factor time) and one quasi-experimental independent factor (SVR versus no SVR). Due to the nature of the independent factor (SVR versus no SVR), randomization was not feasible in our study.

All participants received antiviral combination treatment after study enrolment and a baseline evaluation[15]; the treatment consisted of weekly subcutaneous injections of pegylated interferon (peginterferon alpha-2b: Pegintron 1.5 μg per/kg of body weight per week) and weight-adapted ribavirin (Rebetol 800-1,200 mg daily, given orally) for 24 weeks (genotypes 2 and 3) or for 48 weeks (genotypes 1 and 4). During the study period, we adopted a more flexible treatment regimen for a subgroup of our patients according to changing recommendations: HCV type-1 infected patients with a low viral load before treatment (<600,000 IU/mL) who became virus-negative at treatment week 4 (rapid virologic response [RVR]) were treated for only 24 instead of 48 weeks.[15, 16] This shortened treatment duration was approved in the European Union (EU) in 2005.[15] The latter information was added to the original study protocol as an amendment. An SVR was defined as a negative PCR assay 24 weeks after completion of antiviral therapy for chronic HCV infection.

Neuropsychological Testing

Neurocognitive and attentional performance were assessed using a set of computer-assisted psychological tests (TAP: Test for Attentional Performance; v. 1.02c[19, 20]).

The tasks consist of simple and easily distinguishable stimuli that the patients react to with a simple motor response. Based on a previously published study by our group,[10] the four most relevant (from a total of 12) computerized tasks were selected to monitor cognitive functions during treatment and follow-up periods (listed in the order of subtask presentation):

· Alertness (10 minutes): This examination includes a simple and a cued reaction time task (visual test stimulus with and without an additional acoustic cue). The simple reaction time has been shown to be a valid measure of general slowness, whereas the difference between a simple and a cued reaction time is a measure of phasic alertness. The visual stimulus consists of a white cross on a black background presented approximately every 3 seconds.

· Divided Attention (5 minutes): Divided attention (simultaneous attention to various aspects) can be investigated using so-called dual tasks, including independent visual and acoustic tasks. The visual task consists of crosses that appear in a random configuration in a 4 x 4 matrix. The subject is asked to detect whether the crosses form the corners of a square. The acoustic task consists of a regular sequence of high and low beeps. The subject is asked to detect any irregularity in the sequence.

· Vigilance (20 minutes): Sustained attention is assessed as follows: out of a series of monotonously presented acoustic and visual stimuli (alternating beeps and letters over a time period of 15 minutes), the patient must press a button if the sequence "high beep followed by E" or "low beep followed by N" occurs.

· Working Memory (15 minutes): This test measures the subject's ability to manage a continuous flow of information with short-term memory. Numbers are presented on the screen that must be compared with previously exposed numbers. The subject must identify the repetition of a number within a short interval by pressing a key. The subject is asked to press the key when the presented number equals the number before the previous one.

Statistical Analysis and Sample Size Considerations

All statistical analyses were performed at the study's data coordinating center, located in Wurzburg University (Medizinische Klinik und Poliklinik II, Department of Gastroenterology, Wurzburg, Germany). Data management and all statistical analyses were performed using SPSS software (German v. 15.0.1[21]). The primary endpoint was the neurocognitive performance of the patients in each subgroup (SVR versus no SVR) 48 weeks after the end of the antiviral combination therapy. The primary analysis upon which the sample size consideration was based involved the comparison of the SVR subgroup and the subgroup of patients without SVR. The sample size calculation assumed a two-factorial design (time course x SVR) with the use of a two-way analysis of variance (ANOVA) analysis, a significance level of 5% and a statistical power of at least 80% to detect a medium effect size (d = 0.5) and thus to show a significant group difference. Based on this background, the optimal sample size was calculated to be a total of 102 subjects. To consider asymmetric subgroups and to allow for a moderate dropout rate and additional calculations (secondary study objectives), we aimed to include a total of at least 150 study participants.

Patients who dropped out of the study were considered as not having reached the primary endpoint. Therefore, their data were not included in the final analyses. In accordance with the above-described study design we used ANOVA analyses to test for changes over time and between-group differences (SVR versus no SVR) in relevant measures of neurocognitive performance (e.g., TAP reaction time). All reported P values are two-sided.

Results

Patients

Beginning in 2002, pretherapeutic psychometric tests were offered to all patients scheduled for antiviral therapy with interferon plus ribavirin at the study center in Wurzburg, Germany. Beginning in 2005, all patients, independent of their treatment outcome, were offered an additional session of psychometric testing to evaluate the possible influence of the treatment outcome on their long-term cognitive function. As defined by the study design, the minimum interval between the end of treatment and the follow-up testing was 12 months (19.1 ± 11.0). A total of 141 patients completed both tests. Fifty-six additional patients were enrolled at the other participating study sites: Med. Klinik I, University of Frankfurt (n = 44), and Klinikum Dresden-Friedrichstadt (n = 12). Therefore, the total size of the study sample was N = 197 patients.

Longitudinal Assessment: Dropout Rate

During the study period, a total of 29 of 197 (14.7%) patients were lost to follow-up. These participants did not show up for the final evaluation of cognitive function after the end of antiviral treatment. They were not included in the final evaluation. Consequently, we were able to include 168 study participants in the final longitudinal analysis. As shown in Table 1, the dropout patients were not significantly different from the remainder of the study population with respect to the majority of the relevant demographic and medical variables assessed. However, male patients were overrepresented in the subsample of study dropouts (72.4 versus 50.6%; P = 0.042).

Approximately 15% of our study patients had liver cirrhosis at the beginning of the study (see Table 1), and all patients were in Child stage A. None of the patients had progressed to stage B or C at the time of the follow-up evaluation, which was at least 12 months after the end of antiviral therapy.

Longitudinal Assessment: TAP Retest Reliability

The short-term retest reliability of the applied TAP subtasks and the magnitude of any potential learning effect were evaluated in a subgroup of patients (n = 50) from the test center in Wurzburg, in whom the pretherapeutic test was repeated after 1 week. The findings are presented in Table 2. The test results were stable and not subject to relevant fluctuation, variation, or a significant effect of training. We found that the neurocognitive measures test battery applied was suitable for the evaluation of neurocognitive changes over time in patients with chronic HCV infection.

Long-Term Evaluation: Possible Bias Related to the Interval Between EOT and Follow-up

The interval between the end of the antiviral treatment and the second psychometric testing varied in the study group from 12 to 48 months. To exclude the possibility that a deterioration of cognitive function due to the progression of the liver disease in the nonresponders might misleadingly appear to indicate a relative improvement in the responders, we examined whether the follow-up period was significantly different between both subgroups. This analysis demonstrated that there was no statistically significant difference (P = 0.697) between the responders (18.9 ± 10.8 months) and the nonresponders (19.5 ± 11.4 months). In addition, there were no changes in the final results when the exact length of follow-up period was taken as a covariate in the statistical analyses (data not shown).

Long-Term Evaluation: Cross-Sectional Comparison

Neurocognitive performance was compared between the subgroups with (n = 116; 69%) and without (n = 52; 31%) SVR. While there was no difference before treatment, the posttreatment neurocognitive performance was better in the group of patients with SVR compared to the patients who had not cleared the virus (Table 3). This difference was statistically significant for reaction times in the TAP subtasks related to vigilance (P = 0.004) and working memory (P = 0.010).

Longitudinal Assessment

According to our primary study objective, we compared changes over time within the subgroups of patients with and without SVR. Using repeated measures ANOVAs, we showed that within the subgroup of sustained responders (n = 116) the neurocognitive performance at the long-term follow-up evaluation was significantly improved in the TAP subtasks related to vigilance, divided attention [optical], and working memory compared to the baseline evaluation. These results are presented in Figs. 1-3.

In the group of patients who did not eliminate HCV (n = 52), the neurocognitive performance did not change significantly after termination of the antiviral treatment compared to measurements at baseline. This applied to all five TAP subtasks performed (0.194 ≤ P ≤ 0.804). However, we also did not detect any significant deterioration of test performance in the nonresponder group as a possible sign of worsening liver function during the study period.

Impact of Liver Histology on Outcome Variables

To control for the possible impact of advanced liver disease, we included the covariate "liver cirrhosis" in the general linear models performed for the detection of longitudinal (baseline versus follow-up) and between-group (SVR versus non-SVR) differences. The variable "cirrhosis" could not be identified as a significant covariate in any of these analyses (P > 0.700), indicating that our results were not biased by liver cirrhosis as a confounding factor.

Discussion

Among the well-documented neurological and psychiatric side effects of interferon, an impairment of cognitive function by this drug during antiviral treatment for chronic hepatitis C has been well documented by us and others.[10, 11, 22] However, evidence from smaller studies suggests that the brain may be affected in patients with chronic HCV infection and noncirrhotic liver disease even before an antiviral treatment has been initiated.[23] These studies have mainly focused on cerebral magnetic resonance imaging (MRI) and functional single photon emission tomography (SPECT) neuroimaging in infected patients in comparison with healthy controls. From their results it remains unclear whether the hepatitis C virus per se has a direct effect on cerebral function, or whether the impairment is caused by the chronic inflammation in the liver.

Quantitative data on functional impairment are less frequent,[27, 28] and only few data are available describing the potential reversibility of cognitive disturbances associated with chronic HCV infection.[12]

Therefore, this study examined pretreatment and posttreatment cognitive functions in patients with chronic HCV infection. We used a computerized test battery to quantify even small effects of permanent virus elimination on neurocognitive performance. The TAP battery measures the patients' reaction with a simple motor response to simple and easily distinguishable stimuli. It has been shown that the test is not influenced by a significant learning effect[19, 20] and is therefore applicable for longitudinal comparisons in a repeated-measures design. This was again confirmed in a subgroup of patients in this study, in whom we demonstrated the stability of performance without a relevant learning effect, even when the test was repeated after only 1 week (Table 2). In a previous study on antiviral therapy in HCV-infected patients, we used the TAP test battery to assess and quantify the negative but fully reversible effects of interferon-based therapy on neurocognitive performance.[10]

In our study, we identified a comparatively high rate of sustained responders (116 of 168 patients, SVR 69%). This might be explained to some extent by the fact that due to the study design no dropouts during the treatment phase were included (i.e., these represent per protocol rather than intention-to-treat data). In addition, our response rate corresponds well to published data for well-motivated and treatment-adherent patient groups. McHutchison et al.[29] published an SVR of 63% for a group (majority genotype 1) that received at least 80% of their medications over at least 80% of the time.

We observed a significant improvement of neurocognitive function measured at least 1 year after the completion of a successful antiviral therapy. However, in nonresponders or in patients that relapsed after treatment with interferon/ribavirin, there was no significant change of performance in any of the TAP subtasks. From this, it can be concluded that the cognitive impairment in patients with active HCV infection is potentially reversible. This result is further supported by the fact that we were able to exclude the exact duration of the follow-up period as a possible confounding factor. Remarkably, the posttreatment improvement consisted of only the more complex and demanding TAP subtests. The task "divided attention: optic" requires continuous visual scanning of the computer screen for predefined patterns, while in the task "divided attention: acoustic," where no posttreatment improvement was noted, the (acoustic) signals are more readily available to the sensorium. Equally, the subtask "vigilance" is characterized by the presentation of monotonous signals over 15 minutes, and the performance is therefore sensitive to a condition with an increased fatigability, as has been described for chronic hepatitis C.[30, 31]Similarly, the subtask "working memory" requires the continuous concentration of the subjects on a sequence of numbers that is presented optically. While the pretreatment performance in all tests was identical in both patient groups, the patients after successful antiviral therapy had significantly better results in the above-mentioned subtasks "vigilance" and "working memory" in a cross-sectional comparison performed at least 1 year after treatment.

The study design chosen does not allow for an in-depth investigation of the possible underlying mechanisms. Plausible explanations for the SVR-associated neurocognitive improvement refer to either direct neurotoxicity of the HCV or indirect mechanisms mediated by HCV-triggered or inflammation-triggered induction of cytokine cascades. In an earlier study we demonstrated that a similar pattern of neurocognitive impairment, although considerably more pronounced than in the present investigation, occurs in HCV patients during high-dose IFN therapy.[10] However, it is controversial whether endogenous IFN production is induced during chronic hepatitis C infection. While it has been demonstrated in vitro that IFN production may be impaired by HCV,[32] another study found elevated IFN serum titers in approximately half of infected patients.[33] Therefore, it remains unclear whether IFN or other proinflammatory cytokines confer a cognitive impairment in chronic HCV infection.

Finally, it cannot be excluded that parenchymal recovery following HCV eradication might be responsible for the observed effects because comparative pretreatment and posttreatment liver biopsies were not taken.

Our findings are consistent with previously published results from smaller studies suggesting that HCV-associated neurocognitive decline may be reversible after viral clearance: For example, Forton et al.[28] were able to demonstrate that the ability to concentrate and the speed of memory processes were significantly impaired in patients with chronic HCV infection compared to healthy controls. In contrast, the authors found no difference in neurocognitive performance between healthy controls and former HCV patients who had cleared the virus. However, the study had a small sample size (27 viremic HCV patients and 16 patients after virus clearance) and represented a cross-sectional study approach.

Interestingly, there are also reports suggesting that chronic fatigue and cognitive dysfunction may persist in several patients even after successful clearance of the HCV virus.[13, 26] The question whether a cognitive deficit persisted even in our group of successfully treated patients compared to individuals who had never been infected cannot be answered. For this, a representative and well-matched control group would have been necessary. In conclusion, our data confirm previous reports that in patients with chronic HCV infection, neuropsychological performance is affected not only by high-dose interferon alpha-2b therapy,[10, 34] but also by the infection per se; furthermore, this latter impairment is potentially reversible after successful virus eradication. Thus far, the prevention of liver cirrhosis and its consequences have been the main goal of antiviral therapy in patients with chronic HCV infection. We suggest that the potential benefit of a successful therapy for chronic hepatitis C with respect to the patients' neurocognitive function should be considered as an additional treatment indication in this disease.

The aim of further studies would be to clarify the exact mechanisms that link HCV infection and neurocognitive function.

Source