Psychosocial assessment and monitoring in the new era of non-interferon-alpha hepatitis C virus treatments

World J Hepatol 2015 September 8; 7(19): 2209-2213
World J Hepatol. 2015 September 8; 7(19): 2209-2213.
Published online 2015 September 8. doi: 10.4254/wjh.v7.i19.2209.
Copyright©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.

Psychosocial assessment and monitoring in the new era of non-interferon-alpha hepatitis C virus treatments
Paul J Rowan and Nizar Bhulani

Abstract
Chronic hepatitis C virus (HCV) is a global concern. With the 2014 Food and Drug Administration approvals of two direct-acting antiviral (DAA) regimens, ledipasvir/sofosbuvir regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir regimen, we may now be in the era of all-pill regimens for HCV. Until this development, interferon-alpha along with Ribavirin has remained part of the standard of care for HCV patients. That regimen necessitates psychosocial assessment of factors affecting treatment eligibility, including interferon-alpha-related depressive symptoms, confounding psychiatric conditions, and social aspects such as homelessness affecting treatment eligibility. These factors have delayed as much as 70% of otherwise eligible candidates from interferon-based treatment, and have required treating physicians to monitor psychiatric as well as medical side effects throughout treatment. All-pill DAA regimens with the efficaciousness that would preclude reliance upon interferon-alpha or ribavirin have been anticipated for years. Efficacy studies for these recently approved DAA regimens provide evidence to assess the degree that psychosocial assessment and monitoring will be required. With shorter treatment timelines, greatly reduced side effect profiles, and easier regimens, psychosocial contraindications are greatly reduced. However, current or recent psychiatric comorbidity, and drug-drug interactions with psychiatric drugs, will require some level of clinical attention. Evidence from these efficacy studies tentatively demonstrate that the era of needing significant psychosocial assessment and monitoring may be at an end, as long as a manageable handful of clinical issues are managed.

Keywords: Depression, Therapy, Psychiatry, Clinical, Direct-acting antivirals

Core tip: The recently Food and Drug Administration approved direct-acting antiviral regimens for hepatitis C virus (HCV), ledipasvir/sofosbuvir regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir regimen, have demonstrated great efficacy, and thus far seem to have short treatment timelines and relatively benign side effect profiles. Depression has not emerged as a side effect of these treatments. With efficacious regimens that include no interferon-alpha and no ribavirin, there may no longer be a need for strong psychosocial assessment and monitoring built into the routine of HCV treatment. Good history-taking, strong pharmaceutical review, and reliable consultative relationships should be adequate for meeting psychosocial needs in HCV treatment.

INTRODUCTION
Chronic hepatitis C Virus (HCV) is a global concern, with approximately 170 million people affected worldwide. It is the leading cause of liver cirrhosis in developed countries[1,2]. Of the 6 genotypes, genotype 1 is the most prevalent[3]. Interferon alpha was recognized as a successful treatment in the 1980s, but success rates were low. Since 1998, Interferon-alpha along with ribavirin has remained the standard of care for HCV infected patients, with success rates in genotype 1 only at approximately 40%, while success rates for genotypes 2 and 3 hover around 80%. Until recently, the only significant change to this regimen was the approval of pegylated interferon-alpha treatment, in 2001, making the regimen less challenging by reducing injections per week and boosting efficacy to some degree.

Due to side effects of this regimen, candidates must be assessed for eligibility. As much as 70% of otherwise eligible patients are not eligible to begin treatment due to contraindications[4,5]. A leading contraindication has been depression, since a leading side effect is the depression that may emerge or be exacerbated by interferon-alpha. Clinicians have also had to monitor other psychosocial issues, such as substance abuse. Some evidence suggests that treatment does not seem to work in active alcohol users[6], although some assessment have shown similarly successful outcomes regardless of current alcohol abuse[7]. Injection drug users have been perceived as at risk for insufficient adherence[8], and also at risk for re-infection[9], so this poses another area of psychosocial assessment. Clinically, a common practice has been to refer an otherwise eligible candidate for psychiatric care when any of these psychiatric conditions are present or have been recently active.

Another psychosocial concern is social stability: since treatment may take as long as 48 wk, a candidate must have stable housing and have means for refrigerating the interferon-alpha. Those with unstable housing or unstable income might need to have those issues addressed by social work before treatment can be initiated. For women of child-bearing age, the teratogenic risk of ribavirin requires attention to pregnancy risk. A recommended practice has been to assure mandatory birth control adherence for any woman of child-bearing age to be prescribed any extended regimen that includes ribavirin[10]. Thus, while the prevailing regimen promises good outcomes for many, psychosocial assessment and monitoring has been a necessary part of HCV treatment.

Major changes to this clinical picture began in 2011, with approval of the first direct-acting antivirals (DAA), boceprevir and teleprevir. While these drugs greatly boosted genotype-1 success rates and shortened treatment time by months, these successes were gained by augmenting an interferon-alpha and ribavirin regimen with these newer drugs. So, patients still faced the side effects and contraindications associated with interferon-alpha and with ribavirin.

With the 2014 Food and Drug Administration (FDA) approvals of the ledipasvir/sofosbuvir “Harvoni” regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir “Veikira Pak” regimen, and with more regimens under development, we may now be in the era of all-pill regimens for HCV. Compared to the prevailing standard of interferon-alpha-plus-ribavirin regimen that has prevailed since the 1990s, this advancement in HCV treatment is revolutionary for a few reasons: these new regimens have superior efficacy across genotypes; the treatment timeline is relatively brief; and patients no longer need to self-administer a medication by injection. Also, a further advancement seems to be the favorable side effect profile.

Clinics treating HCV patients have had to develop the capacity to provide the noted psychosocial assessment and monitoring. With the advent of these new regimens, it is worth reviewing their side effect profiles to consider the degree that psychosocial assessment and monitoring will continue to be part of HCV treatment. This requires examining how lengthy and complex any regimen is, the rates of discontinuation, the degree of psychiatric adverse events experienced by study enrollees, and whether any regimen medications have any psychosocial contraindications (e.g., homelessness, risk of pregnancy). This review draws upon previously published data, and no original data, so no institutional review board approval was needed, and no consenting of any participants was required; it is also noted that the authors have no conflicts of interest.

Ledipasvir-sofosbuvir regimen: Psychosocial aspects
The ledipasvir-sofosbuvir regimen, commercially available as Harvoni®, received FDA approval on October 10, 2014. The ION series of studies[11] established safety and efficacy for this regimen. ION-1 allowed individuals with mental illness to enroll, as long as the condition had been well-controlled for at least a year. Also, exclusion criteria included those with any psychiatric hospitalization, suicide attempt, or psychiatric disability period in the recent five years (ION-1 Study Protocol, 4.3 g). A positive drug screen, elevated AUDIT (excessive-alcohol screener) score, or drug abuse in the recent 12 mo were also exclusionary criteria. Therefore, enrollees could have a mental illness such as depression, but had to be free from recent complications of that condition. In the ION-1 study, there was no drop-out due to side effects (one enrolled participant dropped out after only one dose), and only 4 of the 431 participants receiving the ledipasvir-sofosbuvir regimen regimen were lost to follow-up: loss to follow-up can reflect any of many factors, including a passive refusal to continue a regimen due to side effects or a regimen that is too complex. This rate of loss to follow-up is much lower than interferon-based trials. In the initial study providing the superiority of pegylated interferon, by Fried et al[12], 677 participants were randomized and began treatment in the two pegylated interferon arms (one with ribavirin, one with placebo); of these, 145 (21.4%) experienced depression, and 28 (4.1%) discontinued treatment (20 refused to continue treatment at some point after beginning, and 8 had failure to return). About the same time, a similar efficacy study of pegylated interferon-alpha was conducted by Manns et al[13]. In this study, 30% of the 1025 patients in the two study arms receiving pegylated interferon-alpha experienced depression symptoms. In another analyses of these data[14], the researchers noted that 218 of 1010 (21.6%) patients receiving interferon-alpha sustained treatment for less than 80% of the planned treatment time span. Thus, depressive side effects and other aspects of interferon-based regimens have been challenging for patients to tolerate. For the ledipasvir-sofosbuvir regimen, low rates of discontinuation may also be due to the ease of compliance with the regimen: both medications are combined in one pill, taken orally once daily.

In the ION-1 trial, no psychiatric serious adverse events were reported among participants taking the ledipasvir-sofosbuvir regimen, although other serious adverse events, such as chest pain and pneumonia, occurred in a few of these patients. Thus, overall, there does not yet seem to be any notable risk of psychiatric symptomatology for the ledipasvir-sofosbuvir regimen, per study adverse event reporting or as might be suggested by drop-out/loss to follow-up or by adherence data. These study data indicate that, so far, psychiatric problems such as depressive symptoms do not seem to be a side effect of treatment, although it must be acknowledged that study criteria excluded those with current or recent psychiatric difficulty.

A related study, ION-3, was conducted to determine whether a more brief regimen, 8 wk vs 12 wk of ledipasvir-sofosbuvir, could be as efficacious[15]. This study, with a protocol largely parallel to ION-1, included 215 participants in the 8 wk ledipasvir-sofosbuvir arm and 216 in the 12 wk arm. Among these participants, the study’s Supplementary Materials indicate no psychiatric adverse events, and report very low rates of drop-out/loss-to-follow-up (4 of 431; 0.9%). So, again, the ledipasvir-sofosbuvir regimen seems very unlikely to produce psychiatric adverse events, or to have treatment discontinuation.

Is pregnancy risk a concern for the ledipasvir-sofosbuvir regimen, as for the interferon-alpha/ribavirin regimen? Thorough data, such as a randomized clinical trial with pregnant women, have not been conducted, and post-marketing surveillance is still young, so human data are limited. The FDA-approved medication insert data report that animal-model studies have failed to find any teratogenic effect when given to rats or rabbits at exposures that are 3 or more times greater than human doses. The status for pregnant women is currently Category B: animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Does the ledipasvir-sofosbuvir regimen have contraindications with any psychiatric medications, requiring close scrutiny in patients prescribed psychiatric medications? Prescribing information report no such noted conflicts, and neither of the two component medications have metabolism by cytochrome P450 genes, a common biological indicator of possible drug-drug difficulties for psychiatric medications. Post-marketing surveillance has been brief, but thus far contraindications for psychiatric medications have not been detected for this regimen.

Ombitasvir-paritaprevir-ritonavir and dasabuvir: Psychosocial aspects
Ombitasvir-paritaprevir-ritonavir plus dasabuvir is commercially available as Viekira Pak®, which is a once daily pill of ombitasvir-paritaprevir-ritonavir and a twice daily pill of dasabuvir[16]. Two related studies with similar protocols, PEARL-III and PEARL-IV[16], assessed the efficacy and adverse events of this regimen. Each studied the ombitasvir-paritaprevir-ritonavir plus dasabuvir regimen with or without ribavirin in randomized, placebo-controlled trials. PEARL-IV studied patients with genotype 1a, and PEARL-III studied those with genotype 1b. The placebo arms (no ribavirin) of each of these studies provide relevant data regarding possible psychosocial issues to be assessed and monitored in this no-interferon-alpha, no-ribavirin regimen.

Potential participants with current or recent alcohol or substance abuse (recent 6 mo) were excluded, but otherwise psychiatric comorbidity was not an exclusion. Together, in the placebo arms (no ribavirin), there were 414 participants who participated in 12 wk treatment. Aside from those discontinuing treatment due to virologic failure or to adverse events that had no psychosocial aspect, there were only 6 (1.4%) who did not complete treatment (consent withdrawn, lost to follow-up, or “other” reason). As noted earlier, reason for loss to follow-up cannot be ascertained, but it must be considered that psychiatric side effects or adverse events could be involved. These rates of non-completion are far lower than the rates, noted earlier, for interferon-alpha regimens.

The Supplementary Materials for PEARL-III and IV note adverse events, reported per Medical Dictionary for Regulatory Activities vocabulary. No distinctly psychiatric adverse events are noted except for “memory impairment”, reported by 14 (3.3%) of participants in the no-ribavirin arms of these studies.

So, the ombitasvir-paritaprevir-ritonavir plus dasabuvir regimen seems to be well-tolerated, with strong compliance and a very small burden of psychiatric side effects. Substance abuse may reasonably be a contraindication; more data are likely needed on the degree that those with current or recent psychiatric difficulties may need to be delayed from treatment, but this regimen seems to hold promise for those with psychiatric comorbidities.

There are two well-recognized psychosocial issues with this regimen: the inclusion of ritonavir is problematic for women of reproductive age, and there is a long list of drug-drug interactions between ritonavir and other medications, including several medications used for psychiatric indications. These challenges arise mainly because ritonavir inhibits the liver enzyme cytochrome P450-3A4[17], and so affects to some degree the pharmacokinetics of any drug affected by this enzyme. Extensive data exist regarding pharmacology of ritonavir because it has been recognized for years as part of efficacious human immunodeficiency virus (HIV) treatment[18]. Also, the University of California San Francisco “HIVInsite” website[19] has extensive data on HIV/AIDS drugs, including ritonavir, and is the source of some of the following observations regarding drug-drug interactions.

Ritonavir reduces the efficacy of hormone-based birth control[20,21]. The PEARL study protocols have required that women participating in the trials avoid pregnancy by using at least two forms of birth control, neither of which can be hormone-based. So, along with recognized evaluation for HCV treatment, providers will need to assess and monitor pregnancy risk, and pregnancy prophylaxis, for women of reproductive age.

Many of the ritonavir drug-drug interactions are with medications that have psychiatric indications, including carbamazepine (bipolar disorder), nefazodone (depression), and triazolam (insomnia). So, assessment and monitoring will require surveillance of psychiatric conditions and any medications for these. It is possible that patients taking triazolam for insomnia may not perceive themselves as having a “psychiatric” condition, so merely asking about “psychiatric” diagnoses or prescriptions may not reveal that a patient is using this drug; as is generally advisable, patients should be encouraged to report any and all prescription drugs, as well as over-the-counter drugs and any herbal or “alternative” remedies. Regarding herbal/alternative drugs, patients should avoid taking both ritonavir and John’s Wort[22], a fairly commonly utilized herbal remedy for depression. Ritonavir also has a drug-drug interaction with sildenafil, used for erectile dysfunction; use of both drugs can lead to pulmonary arterial hypotension, and there are drug-drug interactions with other drugs used for erectile dysfunction as well, including avanafil, tadalafil, and vardenafil. There is a fair amount of clinical folklore and evidence that sildenafil is misused for recreational purposes[23,24], so the clinical management of HCV treatment that includes ritonavir must assess and monitor the use of erectile dysfunction drugs, whether this use is legitimate use or recreational use.

In conclusion, clinical trial data indicate that these recently approved, all-pill, no-interferon-alpha/no ribavirin regimens are far more readily tolerated by patients generally, and do not seem to have notable psychiatric contraindications. Challenges of these regimens may be limited to examining drug-drug interactions, including the prescription of drugs for psychiatric indications or for birth control. None of these issues requires significant involvement of specialty mental health or social work professionals, although it is necessary to have these services readily available by consultation.

The type of psychosocial assessment and monitoring required for these regimens is typical in medical care delivery, and the adoption of the electronic medical record and e-prescribing can support the detection of potential drug-drug interactions. In many cases, precautions or alternative clinical management strategies can be determined for the duration of the 12 wk treatment, in consultation with a pharmacist, the prescriber overseeing the psychiatric condition, or both. So, with these recently FDA-approved DAA regimens for HCV, with no interferon-alpha and no ribavirin, treatment settings may no longer need to have strong psychosocial assessment and monitoring built into the routine of HCV treatment.

There are some further research issues to be assessed for these recently-approved DAA regimens. As clinical experience builds with all-pill DAA regimens, the experience of patients with well-controlled or poorly-controlled psychiatric comorbidity should be noted and reported. One or both of these regimens may be well-tolerated in patients with a range of psychiatric comorbidities. If the DAA regimens are well-tolerated by those with current or recent psychiatric comorbidities, this would greatly broaden the range of patients eligible to initiate therapy. Also, it would be valuable to investigate patient preferences for avoiding pregnancy for the duration of treatment. As evidence builds, we will be able to more firmly determine whether we have entered an era in which there is no longer any great need for psychosocial assessment and monitoring of patients undergoing HCV treatment.

Footnotes
P- Reviewer: Garcia-Elorriaga G, Isamu S S- Editor: Qiu S L- Editor: A E- Editor: Liu SQ
Conflict-of-interest statement: The authors have no conflicts of interest.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Peer-review started: July 5, 2015
First decision: July 31, 2015
Article in press: August 31, 2015

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Assessing cardiovascular risk in hepatitis C: An unmet need.

World J Hepatol 2015 September 8; 7(19): 2214-2219

Assessing cardiovascular risk in hepatitis C: An unmet need.
Javier Ampuero and Manuel Romero-Gómez.

Abstract

Chronic hepatitis C virus (HCV) is associated with significant morbidity and mortality, as a result of the progression towards cirrhosis and hepatocellular carcinoma. Additionally, HCV seems to be an independent risk factor for cardiovascular diseases (CVD) due to its association with insulin resistance, diabetes and steatosis. HCV infection represents an initial step in the chronic inflammatory cascade, showing a direct role in altering glucose metabolism. After achieving sustained virological response, the incidence of insulin resistance and diabetes dramatically decrease. HCV core protein plays an essential role in promoting insulin resistance and oxidative stress. On the other hand, atherosclerosis is a common disease in which the artery wall thickens due to accumulation of fatty deposits. The main step in the formation of atherosclerotic plaques is the oxidation of low density lipoprotein particles, together with the increased production of proinflammatory markers [tumor necrosis factor-α, interleukin (IL)-6, IL-18 or C-reactive protein]. The advent of new direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis C infection. In this scenario, the cardiovascular risk has emerged and represents a major concern after the eradication of the virus. Consequently, the number of studies evaluating this association is growing. Data derived from these studies have demonstrated the strong link between HCV infection and the atherogenic process, showing a higher risk of coronary heart disease, carotid atherosclerosis, peripheral artery disease and, ultimately, CVD-related mortality.

Keywords: Hepatitis C, Atherosclerosis, Coronary artery disease, Cardiovascular risk, Oxidative stress, Inflammation

Core tip: Chronic hepatitis C is associated with significant morbidity and mortality, as a result of the progression towards cirrhosis and hepatocellular carcinoma. Furthermore, hepatitis C virus seems to be an independent risk factor for cardiovascular diseases due to its association with insulin resistance, diabetes and steatosis. The advent of new direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis C infection. In this scenario, the cardiovascular risk has emerged and represents a major concern after achieving the eradication of the virus.

INTRODUCTION

Hepatitis C virus (HCV) infection is a global health problem that affects 170 million people worldwide. Hepatitis C is responsible for about 100000 deaths annually[¹]. Chronic hepatitis C is associated with significant morbidity and mortality, which result mainly from the progression towards cirrhosis and hepatocellular carcinoma[²]. Extrahepatic manifestations are well-known complications of HCV infection. Similar to non-alcoholic fatty liver disease[^3,4], HCV seems to be an independent risk factor for cardiovascular diseases (CVD) due to its association with insulin resistance, diabetes and steatosis[⁵]. However, our knowledge about this topic requires further studies. In fact, previous studies that assessed the association between HCV infection and CVD risk have been sometimes inconclusive[⁶]. In this review, our aim is to elucidate the role of HCV infection on the cardiovascular-related affectation.

HCV AND INFLAMMATION

HCV infection represents an initial step in the chronic proinflammatory cascade. It produces proinflammatory cytokines, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) alpha, leading to increased inflammation and liver fibrosis. In addition, HCV-related steatosis promotes increased expression of inflammatory markers. These molecules are able to inhibit the insulin signaling, causing insulin resistance and steatosis progression[⁷].

Insulin resistance

Several studies have established a direct role of HCV in altering the glucose metabolism, leading to insulin resistance and diabetes, especially in genotype 3[⁸]. This relationship could explain, at least in part, the impact of metabolic abnormalities on sustained virological response (SVR), regardless of other variables such as viral or IL28B genotypes. In fact, achieving SVR with antiviral therapy results in a dramatically decrease of the development of insulin resistance and the appearance of diabetes mellitus over time[⁹].

HCV core protein plays a fundamental role in the induction of insulin resistance. The PI3K/Akt pathway, whose phosphorylation is impaired upon insulin stimulation, is crucial for the inhibition of gluconeogenesis in the liver. HCV core protein is able to degrade the insulin receptor substrates (IRS) 1 and 2, by increasing the expression of TNFα and suppressing cytokine signalling-3, leading to defective downstream PI3K and Akt phosphorylation[¹⁰]. In fact, when viral clearance is obtained, the expression of IRS-1 and IRS-2 is restored and HOMA-IR index decreases, which indicates the independent role of HCV in insulin resistance[¹¹]. Furthermore, there are other non-structural proteins, like NS5A and NS5B, which also promote insulin resistance, enhancing TNFα and IL-6. The ability of these molecules to disturb insulin signaling is well recognized. IL-1β is other interesting molecule. It is produced by hepatic macrophages, and is related to liver inflammation and, ultimately, to disease progression[¹²]. Finally, the role of toll-like receptors is growing in importance. HCV infection activates these molecules, which are closely associated with proinflammatory cytokines, contributing to the vicious circle[¹³].

Oxidative stress

Oxidative stress is the other main pathway of HCV-mediated inflammation, as insulin resistance promotes fatty acid accumulation in the liver, resulting in increased β-oxidation and reactive oxygen species (ROS)[¹⁴]. On the one hand, mitochondrial fat oxidation upregulates nuclear factor κB (NF-κB). This latter activates the transcription of several proinflammatory genes and the production of proinflammatory cytokines[¹⁵]. On the other hand, ROS play an important role in fibrogenesis by proliferating hepatic stellate cells and collagen synthesis and by inducing tumor growth factor-β[¹⁶]. An imbalance between oxidant agents and antioxidant defenses is the final result of all these processes, causing oxidative damage to hepatocyte and altering the reparation of DNA.

ATHEROSCLEROSIS

Lipid oxidation

Atherosclerosis is a common disease in which the artery wall thickens due to the accumulation of fatty deposits, called atheromatous plaques. Cholesterol-rich low density lipoprotein (LDL) is the main atherogenic lipoprotein. LDL infiltrates into the endothelium and adheres to extracellular matrix components, resulting in accumulation in the vascular intima[¹⁷]. Interestingly, LDL particle size seems to facilitate the passing between the endothelial cells because small dense LDL represents a major component of an atherogenic lipoprotein phenotype[¹⁸].

The main step in the formation of atherosclerotic plaques is the oxidation of LDL particles, being the risk higher in the wall than in the bloodstream[¹⁹]. Monocytes penetrate into endothelium and are able to transform into macrophages. This latter kind of cells is able to phagocyte oxidized LDL (oxLDL) particles triggering a cascade of immune responses and producing an atherosclerotic plaque[²⁰]. During oxidation, LDL converts to oxLDL involving some enzymes (such as lipoprotein-associated phospholipase A2) with several consequences: (1) oxLDL activates T cells and macrophages, stimulating the production of foam cells; (2) oxLDL induces the expression of endothelial adhesion molecules and the stimulation of several growth factors; and (3) oxLDL affects nitric oxide releasing and vascular smooth muscles, contributing to impair the vascular contraction[²¹]. As a result, oxLDL is able to thicken the intima and enhance atherosclerosis.

Inflammation

Many markers, such as proinflammatory cytokines (TNFα, IL-6 and IL-18), C-reactive protein, and adhesion molecules, are increased in plasma in situation of chronic inflammation. C-reactive protein may promote inflammation and atherogenesis through effects on monocytes and endothelial cells[²²]. Regarding to proinflammatory cytokines, TNFα activates NF-κB after interacting with the vascular endothelium[²³]. On the other hand, there are other cells with the capacity of enhancing proinflammatory cytokines such as activated macrophages, Th1 lymphocytes, and foam cells. Furthermore, several receptors (i.e., CD-36 and toll-like receptors) located on the membrane of macrophages leads to uncontrolled phagocytosis of oxLDL[²⁴].

Diagnostic tests

Noninvasive and inexpensive tests to anticipate and facilitate the prediction of cardiovascular risk are growing in importance. Atherosclerosis can be detected by several methods, depending on the organ or tissue affected. Carotid intima-media thickness and the presence of carotid plaques serve as marker of subclinical atherosclerosis and can be measured by ultrasound. They are especially considered to be independent stroke predictors[²⁵] and related to cardiovascular events[²⁶]. Other tests have been developed with the same proposal. Coronary artery calcification, judged by computed tomography, is a good predictor of coronary heart disease[²⁷]. Brachial artery flow-mediated vasodilation is a test of endothelial dysfunction that is associated with early stages of atherosclerosis[²⁸]. Pulse-wave velocity seems to be the gold standard of arterial stiffness and an early indicator for atherosclerosis[²⁹]. Other methods, such as left ventricular hypertrophy (by electrocardiogram and echocardiogram)[³⁰] or peripheral arterial disease (PAD) (by ankle-brachial pressure index)[³¹], are not extended in clinical practice due to costs or specialized personal requirement.

BIOLOGICAL MECHANISMS LINKING HCV AND ATHEROSCLEROSIS

A large body of evidence shows that infective agents contribute to promote chronic inflammation which could be associated, ultimately, with atherosclerosis[³²]. Therefore, HCV infection has been widely assesed and biological mechanisms have been reported.

On the one hand, HCV infection seems to be associated with a higher risk of cardiovascular disease by indirect mechanisms. Firstly, HCV infection is strongly associated with metabolic abnormalities, including diabetes mellitus and liver steatosis, as well as metabolic syndrome. All of these risk factors are well-known predictors of cardiovascular disease[³³]. Secondly, HCV infection interrelates with the host immune response. As it is commented above, it is able to stimulate the production of proinflammatory cytokines[³⁴]. Thirdly, HCV infection comprises other extra-hepatic manifestations. In particular, cryoglobulinemia has been associated with higher prevalence of arterial hypertension and CVD compared to those patients without this entity[³⁵].

On the other hand, the HCV seems to be directly related to atherosclerosis. HCV RNA sequences have been investigated by highly sensitive reverse transcriptase-polymerase chain reaction in plaque tissues of patients who underwent to carotid revascularization, demonstrating the presence of genomic and antigenomic HCV RNA strands. Consequently, additionally to the role of HCV on the development of chronic inflammation due to insulin resistance and steatosis, HCV RNA sequences seems to play a local effect on the endothelium[³⁶].

IMPACT OF HCV-RELATED ATHEROSCLEROSIS

Coronary heart disease

Several studies have investigated the association between atherosclerosis and HCV infection, with conflicting results. In a systematic review, the majority of studies were of poor quality although revealed a tendency towards a higher risk of coronary heart disease (CHD) among patients with HCV infection. However, the studies showed heterogeneity in terms of methods and conclusions[³⁷]. Other studies have showed similar conclusions. Forde et al[³⁸] did not observe any difference in the incidence rates of CHD between HCV-infected and uninfected patients, as well as in terms of coronary revascularization procedures. Main limitation of studies showing no HCV-related effect on CHD is the inclusion of some patients who could have had spontaneously cleared HCV infection.

There are no many studies differentiating HCV antibody and RNA positivity, regarding to CHD events. In a very large study, authors found an increased risk of CHD in patients with HCV seropositivity, being an independent risk factor for CHD events. HCV seropositive patients had a higher incidence of CHD events compared with controls (4.9% vs 3.2%). Additionally, patients with detectable HCV-RNA had a significantly higher incidence of CHD events compared with patients who were only HCV antibody positive (5.9% vs 4.7%). Therefore, there was an increased incidence of CHD events in patients with HCV seropositivity and the incidence was much higher in patients with detectable HCV-RNA compared with patients with remote infection who were only antibody positive[³⁹]. 

Electrocardiogram abnormalities are strongly associated with cardiovascular disease. HCV infection has been associated with increased risk to ischemic electrocardiogram when compared with non-HCV subjects, revealing a possible relationship between HCV seropositivity and ischemic electrocardiogram[⁴⁰]. Other study, performed by Butt et al[⁴¹], demonstrated that HCV-infected subjects had lower lipid levels and a lower prevalence of hypertension than those non-infected. Despite a favorable risk profile, HCV infection was associated with a higher risk of CHD after adjustment for traditional risk factors. In diabetic population, similar results have been obtained. Authors included three cohorts: patients who received pegylated interferon plus ribavirin (treated cohort), HCV-matched patients (untreated cohort) and diabetic patients without HCV infection (uninfected cohort). Main conclusion was that the incidences of ischemic stroke and CHD were all lower in HCV-infected patients treated with peginterferon and ribavirin, compared with infected individuals without antiviral treatment and diabetic patients without HCV infection. It is interesting to note that the risk of ischemic stroke and CHD were not attenuated in treated patients with PAD. This finding suggests that the pathogenic role of HCV can be limited at the early phase of atherosclerosis and that antiviral treatment could not reduce cardiovascular morbidity at an advanced stage[⁴²].

Carotid atherosclerosis

A large body of evidence has assessed the association between HCV infection and carotid atherosclerosis. First study was carried out by Ishizaka et al[⁴³], in which they evaluated the relationship between positivity for HCV and carotid-artery plaque and carotid intima-media thickening. After adjustment for cofounding risk factors, HCV seropositivity was found to be associated with an increased risk of carotid-artery plaque (OR = 1.92) and carotid intima-media thickening (OR = 2.85). A definite study was performed by Petta et al[⁴⁴] One-hundred-and-seventy-four consecutive biopsy-proven HCV genotype 1 patients were evaluated by anthropometric and metabolic measurements and other 174 patients used as controls. Authors found that patients with HCV genotype 1 had a higher prevalence of carotid atherosclerosis compared with a control population (carotid plaques: 42% vs 23%; IMT: 1.04 ± 0.21 vs 0.90 ± 0.16). However, no direct association was found between viral load and atherosclerosis. The novel finding was the independent association of the presence of carotid plaques with severe hepatic fibrosis, after adjustment for age. Authors concluded that severe fibrosis and the associated cascade of proinflammatory and profibrogenic pathways generated in the liver might promote carotid atherosclerosis at a much younger age[⁴⁴].

Peripheral artery disease

PAD is an under-diagnosed and under-treated disease. Some data suggest that HCV influences on the presence of PAD. In a retrospective cohort study, 7641 HCV-infected patients and 30564 matched controls were included. An excess risk of PAD development in HCV-infected patients was observed compared with non-HCV patients. The increased incidence of PAD in HCV-infected patients appeared since within first year. This study showed that gender had no effect on the risk of PAD development, but did aging. However, this study showed lack of evaluation of smoking, obesity or exercise[⁴⁵].

Cardiovascular mortality

Given that the HCV infection seems to be related to several atherogenic processes, many authors have evaluated its role on CVD-associated mortality similar to other viral infections[⁴⁶]. Guiltinan et al[⁴⁷] performed a retrospective study including HCV antibody-positive and HCV antibody-negative patients matched for age and gender. HCV infection was associated with a significant increase in overall mortality including significantly increased mortality from liver and cardiovascular causes. In the REVEAL cohort, including 1095 anti-HCV-positive and 760 detectable HCV RNA, was observed that those anti-HCV-positive patients showed a higher risk of CVD-related mortality compared with seronegative subjects[⁴⁸].

CONCLUSION

New direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis C infection[⁴⁹]. Infected patients are going to live longer due to the eradication of the virus, so other HCV-related comorbidities have emerged. Specifically, cardiovascular disease is a major concern in this scenario. All the data provided in this review suggest a strong relationship between HCV infection and the atherogenic process, showing a high risk of coronary heart disease, carotid atherosclerosis, peripheral artery disease and, ultimately, CVD-related mortality. However, little is known about the precise mechanisms by which HCV enhances atherogenic processes. Therefore, we should be cautious when patients achieve SVR because maybe the cardiovascular risk remains after the virus eradication.

Footnotes

P- Reviewer: Balaban YH, Chiang TA, Desai ND S- Editor: Tian YL L- Editor: A E- Editor: Liu SQ

Conflict-of-interest statement: None.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Peer-review started: January 30, 2015

First decision: March 20, 2015

Article in press: August 31, 2015

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Hepatitis C-Salvage Study Grazoprevir and Elbasvir Plus Ribavirin: Final 24-week Follow-up Results

C-SALVAGE: Final 24-week Follow-up Results
Posted on September 17, 2015

Non-cross-resistant drugs are needed for salvage therapy of patients with chronic hepatitis C virus infection who do not achieve sustained virologic response on direct acting antiviral (DAA) regimens. The final follow-up week 24 results from the C-SALVAGE study (Hepatitis C-Salvage Study for Patients who Failed DAA/PR Therapy), have been published in the journal Clinical Infectious Diseases (Buti M, et al. Clin Infect Dis. 2015 Sep 14. [Epub ahead of print]). 

In the C-SALVAGE study, an interferon free combination of grazoprevir (an NS3/4A protease inhibitor) and elbasvir (an NS5A inhibitor) with ribavirin was used to treat patients with chronic HCV genotype 1 infection who had previously failed triple therapy with pegylated interferon and ribavirin plus an earlier-generation protease inhibitor. Both SVR12 and SVR24 were achieved in all but 3 patients who had relapsed by or before follow-up week 8, yielding a durable response rate of 76 of 79 (96.2%), which likely reflects the cure rate.

The international, open-label, phase 2, C-SALVAGE study (Hepatitis C-Salvage Study for Patients who Failed DAA/PR Therapy) established that a non-cross-resistant protease inhibitor such as grazoprevir could be successfully used with a potent DAA of another class to treat patients harboring signature NS3 variants resistant to earlier protease inhibitors. The primary results were recently published in the Journal of Hepatology (Forns X, et al. J Hepatol. 2015;63:564–72).

• 79 patients (including 30 patients with genotype 1a infections [38%] and 34 patients with cirrhosis [43%]) were retreated with grazoprevir 100 mg/day and elbasvir 50 mg/day plus ribavirin after having failed at least 4 weeks of combination therapy with pegylated interferon and ribavirin (PR) plus either boceprevir, telaprevir, or simeprevir
• A total of 66 (84%) patients had a history of virologic failure.
• Despite a high prevalence of NS3 variants at baseline, the overall SVR rate at 12 weeks (SVR12) was 96.2% (76/79) due to 3 patients relapsing during the initial 8 weeks of post-therapy follow-up coincident with the emergence of NS3 ± NS5A RAVs

To exclude the unlikely possibility of late relapses, the correlation between SVR12 and durable viral suppression has been confirmed based on the results obtained at the final follow-up week 24. These results have been published in the journal Clinical Infectious Diseases (Buti M, et al. Clin Infect Dis. 2015 Sep 14. [Epub ahead of print]).

• 78 patients (99%) completed their final scheduled visit at follow-up week 24. One patient who had completed the prescribed course of treatment dropped out of the study at follow-up week 6 after relapsing 4 weeks after cessation of therapy.
• SVR24 was attained in 76 of 79 patients (96.2% [95% CI, 89.3%–99.2%]) overall, in 28 of 30 (93.3%) patients with genotype 1a infection, 63 of 66 (95.5%) patients with prior virologic failure, 33 of 36 (91.7%) patients with baseline NS3 and/or NS5 RAVs, and 32 of 34 (94.1%) patients with cirrhosis. No further relapses occurred subsequent to follow-up week 8, and undetectable HCV RNA levels were maintained in these 76 patients throughout the full 24 weeks of follow up.
• After removal of 9 patients for serious protocol violations during the treatment period, 68 of the 70 (97.1%) patients remaining in the primary per-protocol population achieved SVR24
• 3 patients relapsed during the initial 8 weeks of post-therapy follow-up, coincident with the emergence of NS3 ± NS5A RAVs
  • Every NS3 and NS5A variant detected at baseline reappeared at the time of relapse and persisted throughout the available follow up period, suggesting that virus persisted below the level of detection while on treatment
  • NS3_A156T (conferring >5 times increase in grazoprevir EC50 in vitro) emerged in virus from each patient at relapse, but rapidly disappeared over the ensuing 2 weeks in 2 patients
  • NS5A_Y93H (conferring a >5 times increase in elbasvir EC50 in vitro) emerged in virus from 2 patients at relapse and persisted for the entire follow-up period

The authors concluded the following: “The combination of grazoprevir and elbasvir with ribavirin given orally for 12 weeks offers a new therapeutic option for patients who have failed treatment with pegylated interferon and ribavirin and an earlier protease inhibitor, even in the presence of NS3 variants detectable by population sequencing conferring resistance to the first generation of protease inhibitors. In treatment-naive patients, 12 weeks of grazoprevir/elbasvir without ribavirin produced a 95% SVR12 rate (Zeuzem S, et al. Ann Intern Med. 2015; 163:1–13); the contribution of ribavirin in treatment-experienced patients is being evaluated in a large phase 3 trial nearing completion. Unlike the transiently emergent NS3_A156T variant, NS5A_RAVs at relapse persisted for at least 24 weeks after cessation of therapy. If confirmed in larger numbers of patients, this finding could potentially have implications for the retreatment of the small number of patients who fail combination regimens containing an NS5A inhibitor.”

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