The Clinical Significance of Drug-Drug Interactions in the Era of Direct-acting Anti-viral Agents Against Chronic Hepatitis C

Alimentary Pharmacology & Therapeutics

B. Maasoumy, K. Port, B. Calle Serrano, A. A. Markova, L. Sollik, M. P. Manns, M. Cornberg, H. Wedemeyer

Aliment Pharmacol Ther. 2013;38(11-12):1365-1372.

Abstract and Introduction

Abstract

Background Drug–drug interactions (DDIs) in the treatment of chronic hepatitis C infection became a potential challenge with the introduction of direct-acting anti-virals (DAAs). Both currently approved DAAs, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), are substrates and inhibitors of P-glycoprotein and the cytochrome P450 3A4, which are regularly involved in DDIs.

Aim To analyse the risk for DDIs in patients with chronic HCV genotype 1 infection considered for PI treatment at a tertiary referral centre.

Methods The first 115 consecutive patients selected for a PI therapy at Hannover Medical School were included. All changes to co-medication before and during PI treatment were documented. Drugs were checked for DDIs with TVR and BOC using DDI websites and the respective prescribing information.

Results Out-patient medication contained 116 different drugs. Median number of drugs/patient was 2 (range 0–11). The risk for DDIs was substantial for 38% of the drugs affecting 49% of patients. Only 4% of the drugs were strictly contraindicated. DDIs between a PI and drugs newly prescribed during anti-viral therapy were considerable in 42% of the patients. Suspected DDIs were managed by dose adjustments and discontinuation of co-medication in 7% and 21% of the patients respectively.

Conclusions Many patients with chronic HCV genotype 1 infection are affected by potential DDIs if treated with a protease inhibitor, but only in a minority of cases co-medication is strictly incompatible. Overall, the challenge of DDIs is time-consuming, but well manageable by a careful review of the patient's drug chart and monitoring during treatment.

Introduction

Hepatitis C virus (HCV) infection majorly contributes to the increasing prevalence of liver cirrhosis and hepatocellular carcinoma worldwide.^{[1, 2]} Anti-viral treatment may lead to clearance of the virus, defined as a sustained virological response (SVR). Achieving SVR lowers the risk for hepatic decompensation, hepatocellular carcinoma and reduces overall mortality.^[3-5] The development of direct-acting anti-viral agents (DAAs) has significantly improved HCV therapy, as DAAs increase SVR rates and may soon even lead to interferon-free treatment options.^[6] In 2011, the first generation of this new drug class was approved for the treatment of HCV genotype 1 infection: the protease inhibitors (PI) telaprevir (TVR) and boceprevir (BOC). Since then, the new standard of care for the treatment of chronic HCV genotype 1 infection became triple therapy consisting of pegylated-interferon alpha (Peg-IFN), ribavirin (RBV) and either telaprevir (TVR) or boceprevir (BOC) in many countries. Both PIs markedly improved the probability of SVR compared with previous dual therapy.^[7] Under optimal conditions, up to 88% achieve SVR after 28–48 weeks of triple therapy.^[8-10] However, new PI-containing triple therapies are also accompanied by new problems like a more complicated dosing regimen^{[8, 9]} and a higher number of severe adverse events, in particular, in those with advanced liver disease.^[11-13] Furthermore, with the introduction of DAAs, hepatologists are now facing drug–drug interactions (DDIs) as an additional challenge of HCV therapy. Both approved PIs are strong inhibitors of the cytochrome P450 CYP3A4. Furthermore, TVR and, to a lesser extent, BOC are metabolised by CYP3A4. In addition, both agents are also inhibitors and substrates of the membrane transporter P-glycoprotein (P-gp), which affects TVR more than BOC.^{[14, 15]} As a result, there is a potential risk for DDIs with other drugs metabolised by the same pathways. An increase in drug concentrations may cause toxicity and lead to adverse events. On the other hand, a decrease in drug concentrations may lead to a loss of therapeutic efficacy and, if the PIs are affected, this may lead to treatment failure due to emergence of viral resistance and subsequently a virological breakthrough. Recently, there have been a couple of valuable review articles that indicated drugs that, in principle, should not be administered or only with caution due to anticipated DDIs.^{[14, 15]} However, despite the relative attention DDIs have gained in the discussion of PI therapies, there are rather limited data on the extent that HCV patients are really at risk for DDIs due to their regular out-patient medication. Overall, it remains unclear to what extent DDIs reach clinical significance when HCV patients are considered for DAA treatment. We aimed to investigate the clinical significance of DDIs in a real-life cohort of patients with chronic HCV infection selected for PI treatment in a tertiary referral centre.

Patients and Methods

Patients

The first 115 consecutive patients who were selected to receive treatment with a PI, either TVR or BOC, at the hepatitis out-patient clinic of Hannover Medical School were selected for this study.

Assessment of Drugs Taken before and During PI Treatment

All 115 patients were routinely asked for their regular out-patient medication prior to the start of PI treatment, which importantly also included any kind of self-medication. For the assessment of the out-patient medication at baseline, we documented all drugs that were taken regularly, except for drugs started during Peg-IFN/RBV lead-in phase, which were considered drugs started during anti-viral treatment. In cases of combination products, e.g. ramipril/hydrochlorthiazide, each individual substance was counted separately. In contrast, mixtures of minerals or vitamins as well as herbal medication were counted as only one drug if they contained four or more ingredients. Of the 115 patients, 14 had to discontinue during or directly after the Peg-IFN/RBV lead-in phase due to a virological failure or treatment intolerance. As a result, only 101 patients were exposed to a PI. These 101 patients were followed during PI treatment and all drugs newly taken during or due to anti-viral therapy were assessed.

Estimation of the Risk for Drug-Drug-interactions

All drugs taken before or during PI therapy were carefully analysed for potential interactions with TVR and BOC using the web resource http://www.hep-druginteractions.org, the package label of TVR, BOC and the analysed drug, known interactions with other strong CYP 3A4 inhibitors (using ritonavir and the web resource http://www.hiv-druginteractions.org) as well as additional sources if more information was needed to draw a reliable conclusion. Drugs were categorised into four groups according to the suspected significance of interactions with the PIs: 'No clinically significant interactions expected' (Category 1), 'Interaction possible but in principle manageable by dose adjustments and/or closer monitoring' (Category 2), 'Not recommended for co-administration with a PI' (Category 3) or 'No classification possible due to a lack of information' (Category 0) (Figure 1). In doubt, or in cases of discrepancies between the two HCV PIs, the more sever risk category was chosen.

Figure 1. The four different risk categories of drug–drug interactions with an HCV protease inhibitor: Category 1 (low-risk): 'No clinically significant interactions expected'; Category 2 (significant, but not severe risk): 'Interaction possible but in principle manageable by dose adjustments and/or closer monitoring'; Category 3 (severe risk): 'Not recommended for co-administration with a PI'; Category 0 (uncertain risk): 'No classification possible due to a lack of information'.

Ethics

This study was performed according to principals of good clinical practice as well as the declaration of Helsinki and approved by the local ethics committee of Hannover Medical School.

Results

Patient Characteristics and Anti-viral Treatment

The 115 patients who were selected to receive a PI had a mean age of 54 years and the majority had advanced liver fibrosis or cirrhosis. Overall, only 101 patients were treated with a PI due to a weak response or a poor tolerability to Peg-IFN/RBV therapy in the lead-in phase. A total of 69 patients were treated with TVR and 34 with BOC, including two patients who were switched from TVR to BOC during therapy due to TVR-related adverse events. The median observed PI treatment duration was 12 weeks (range: 4 days–48 weeks) (Table 1).

Table 1.  Baseline characteristics of the study cohort

Patient number	115
Age (mean ± s.d.)	54.4 (±10.3)
Gender
Male	66 (57%)
Female	49 (43%)
Used PI
TVR	69 (60%)*
BOC	34 (30%)*
None	14 (12%)
Duration of PI exposure
Median weeks	12
Min–Max	4 days–48 weeks
Fibrosis stage
F0–F2	24 (21%)
F3/F4	89 (77%)
n/a	2 (2%)
Platelets (mean ± s.d.;/nL)	164 (±69)
Albumin (mean ± s.d.; g/L)	40.8 (±4.3)

s.d., standard deviation; PI, protease inhibitor; TVR, telaprevir; BOC, boceprevir.
*Two patients were switched from TVR to BOC (exposed to both PIs).

Drug-Drug Interactions With the Regular Out-patient Medication Assessed at Baseline

Regular out-patient medication of the 115 patients included 116 different drugs. Almost one of four patients (23%) took more than four different drugs at baseline, while only 29 patients (25%) did not have any regular out-patient medication before HCV treatment was initiated (Figure 2a). Overall, the mean number of regular drugs was 2.7 with a maximum of eleven co-medications. Most commonly used drugs were selective beta-blocking agents, proton pump inhibitors and levothyroxine (Table 2).

Table 2.  The 10 most frequent drug classes in the regular out-patient medication at baseline

Drug class	ATC code (3rd level)	Number of patients (%)
Beta-blocking agents; selective (i.e. bisoprolol)	C07AB	21 (18)
Proton pump inhibitors (i.e. pantoprazole)	A02BC	19 (17)
Thyroid hormones (i.e. levothyroxine)	H03AA	19 (17)
Angiotensin II antagonists (i.e. candesartan)	C09CA	16 (14)
Dihydropyridine derivatives (i.e. amlodipine)	C08CA	15 (13)
ACE inhibitors (i.e. ramipril)	C09AA	15 (13)
Thiazides (i.e. hydrochlorothiazide)	C03AA	11 (10)
Beta-blocking agents; nonselective (i.e. propranolol)	C07AA	10 (9)
Biguanides (i.e. metformin)	A10BA	9 (8)
Propionic acid derivatives (i.e. ibuprofen)	M01AE9	9 (8)

The risk for DDIs with a PI was considered to be negligible (Category 1) for the majority of baseline drugs (62%), whereas for 29%, some DDIs were suspected, but dose modifications or careful monitoring may have been considered as sufficient for management (Category 2). Only 4% of the drugs were contraindicated for co-administration with a PI (Category 3). However, 10% of the patients took one of these contraindicated drugs. In the remaining 5% of the drugs, significant DDIs could not be excluded due to a lack of information (Category 0) (Figure 2b). This majorly affected herbal products and so-called alternative medicine. Overall, 49% of the patients were suspected to be at risk of experiencing significant DDIs, including the 7% of patients taking at least one drug belonging to risk category 0 (Figure 2c). Drug classes most often suspected to be involved in significant DDIs with a PI were thyroid hormones, dihydropyridine derivatives and herbal drugs/alternative medicine (Table 3).

Table 3.  The eight most frequent drug classes in the regular out-patient medication that were suspected to may cause significant drug–drug interactions with an HCV protease inhibitor

Drug class	ATC code (3rd level)	Number of patients (%)
Thyroid hormones (i.e. levothyroxine)	H03AA	19 (17)
Dihydropyridine derivatives (i.e. amlodipine)	C08CA	15 (13)
Alternative Medicine	-	8 (7)
Beta-blocking agents, selective (i.e. bisoprolol)	C07AB	8 (7)
Oestrogens (i.e. ethinylestradiol)	G03CA	3 (3)
Alpha-adrenoreceptor antagonists (i.e. tamsulosin)	G04CA	3 (3)
Glucocorticoids (i.e. prednisolon)	H02AB	3 (3)
Selective serotonin reuptake inhibitors (i.e. escitalopram)	N06AB	3 (3)

Figure 2. Risk for drug–drug interactions between a protease inhibitor and the regular out-patient medication of the 115 patients prior to the initiation of anti-viral treatment: Number of different drugs in the regular out-patient medication (a). Percentage of the different drugs in the regular out-patient medication containing to risk category 1, 2, 3 and 0 for drug–drug interactions with an HCV protease inhibitor (b). Portion of patients with a high risk (taking at least one category 3 drug), an uncertain risk (no category 3, but one or more category 0 drug), significant, but no severe risk (one or more category 2, but no category 0 and 3 drugs) and those without any risk for drug–drug interactions with an HCV protease inhibitor (no or only category 1 drugs in the regular out-patient medication) (c).

Drug-Drug Interactions With Medication Started During Anti-viral Treatment

The included patients received 254 new drugs during PI treatment, mostly due to side effects of triple therapy. Most frequently, these new drugs were specific skin lotions, analgesics or antihistamines. Medications were usually prescribed by the HCV-treating physician, but also frequently by the patient's general practitioners or other physicians. In 8%, the name of the newly prescribed drug could not be evaluated retrospectively affecting 9% of the patients. In only 3% of the patients were new co-medications not suitable for co-administration with a PI. More than half of the patients (59%) either did not take any new drugs during treatment or only those considered to be safe in terms of significant DDIs with a PI (Figure S1a–c).

Impact of DDI Considerations Before and During PI Therapy

In 16% of the patients, at least one drug of the regular out-patient medication was stopped before PI treatment commenced due to suspected DDIs. In an additional 5% of cases, dose adjustments of the respective co-medication were applied before PI treatment was initiated. During PI treatment, discontinuation and dose adjustments of co-medication became necessary each in five cases (5%). Overall, suspected DDIs were managed by dose adjustments and discontinuation of co-medication before or during PI therapy in 7% and 21% of the patients respectively. In six patients (6%), a supposed treatment with certain drugs was either delayed until the end of PI therapy or an alternative medication was chosen due to DDI considerations.

Discussion

Management of drug–drug interactions (DDI) represents a challenge in the treatment of hepatitis C virus (HCV) infection. We here show, in a real-world cohort of patients treated in a tertiary referral centre, that DDIs represent a considerable risk if HCV protease inhibitors (PI) are used. However, DDIs can be managed if adequate medication adjustments and precautions are followed.

DDIs have not been considered a major problem in HCV therapy before HCV protease inhibitors have been introduced in 2011. However, it is certainly not surprising that many HCV patients take several drugs not related to the liver, as documented in our study. Similar to the non-HCV-infected population, HCV patients suffer from different common comorbidities like hypertension, dysliproteinaemia or atrial arrhythmia. Furthermore, some comorbidities like diabetes and thyroid disorders may even be overrepresented in the HCV-infected population, as they have been suspected to be extrahepatic manifestations of HCV infection.^[16-18] Indeed, anti-hypertensive and anti-diabetic drugs as well as thyroid hormones belonged to the most frequent drugs in the regular out-patient medication of our study cohort. However, an important finding of our study was that, although some DDIs were expected in almost half of the patients, only a relatively small portion of patients took drugs that were strictly contraindicated for co-administration with a PI. In addition, a similar number of patients took drugs for which the available drug information was insufficient to exclude DDIs. However, these drugs mainly belonged to herbal products/alternative medicines and therefore a simple discontinuation may widely be considered. Overall, only a minority of patients (n = 23) required adjustments to their pre-treatment medication before or during PI therapy. Based on these findings a careful assessment of the regular out-patient medication and subsequent evaluation of potential DDIs with a PI are absolutely crucial to ensure drug safety in all treated patients. Importantly, this assessment must also include self-medication belonging to the group of herbal products/alternative medicine.

In contrast to the pre-existing baseline medication, the majority of newly prescribed drugs during PI treatment were supposed to counter adverse events of anti-viral therapy. Here, it seems to be feasible to handle potential DDIs by establishing standard algorithms for the management of frequent adverse events like depression or rash. In such standard algorithms, drugs with well-manageable DDIs or, even better, those without any risk for DDIs with a PI should be preferred. As a result of this strategy and careful DDI consideration prior to new drug prescriptions, the risk for DDIs was lower for the newly prescribed medications during PI therapy. Still, of note and importantly, even during PI therapy, some drugs not allowed for co-administration were prescribed by other physicians and, in some cases, drug names were even unknown. This emphasises the need for a close collaboration between different physicians involved in the management of hepatitis C patients.

DDI assessment is certainly rather time-consuming if it is based on several different sources as applied in this study. Still, concentrating exclusively on the prescribing information of BOC and TVR may be insufficient as the provided data are limited. In our experience, web-based DDI interaction tools like http://www.hep-druginteractions.org represent the most feasible and comprehensive way for an assessment of potential DDIs. However, although this web resource is updated regularly and already includes a huge number of drugs, many drugs taken by our study cohort could not be found. This underlines the challenge of generating clinically useful information when comparatively few DDI studies have been performed. Therefore, more studies investigating DDIs with DAAs need to be performed in the future.

This study was not designed to compare the risk of DDIs between TVR and BOC regimens. It is well known that, in general, interactions may be more prominent for TVR. However, overall risk categories of co-medications did not differ between TVR and BOC. In a few cases of doubt or discrepancies between the two HCV PIs, the more severe risk category was chosen, which may have lead to a slight overestimation of the overall risk for DDIs. Certainly, it has to be considered that the current patient cohort may differ from those in smaller centres and may not be representative for all HCV patients due to the referral tertiary setting. As shown in a recently published analysis, patients selected for currently available triple therapy tend to be those with the more urgent need for anti-viral treatment presenting with more advanced liver disease.^[11] However, this shows that, even in a complicated, difficult-to-treat cohort, the challenge of DDI appeared to be manageable. Nevertheless, risk of DDIs must not be neglected. Although only a minority was infected by a severe risk for DDIs, this still requires cautiousness and a careful evaluation of the patient's drug chart. Otherwise, there is a risk for even life-threatening complications. Severe adverse events caused by drug interactions, in particular, through the CYP3A4 pathway are reported frequently.^[19-21] There also have been cases of anti-viral treatment failure in HIV patients due to DDIs.^[22] Lately, there has been a case of renal failure in an HCV-infected liver transplant patient receiving TVR treatment in combination with tacrolimus.^[23] In addition, a possible limitation of our study is that information on number and type of drugs widely depended on patient information. Therefore, some drugs may have been missed and risk for DDIs may have been underestimated in our study.

The next wave of DAAs including the protease inhibitors faldaprevir and simeprevir as well as the NS5B nucleotide inhibitor sofosbuvir may be available in early 2014 and more will follow in the upcoming years. Risk for DDIs differ between the various future DAA classes. The nucleotide NS5B inhibitor sofosbuvir does not seem to be involved in significant DDIs.^{[24, 25]} In contrast, DDIs have to be considered for several nonnucleotide NS5B inhibitors.^[15] DDIs may also play a role for some NS5A inhibitors. Daclatasvir is substrate and inhibitor of P-glycoprotein and substrate of CYP3A4. However, pharmacokinetic data suggest that risk for significant DDIs is far lower compared with using protease inhibitors.^[15] Soon-available PIs faldaprevir and simeprevir are also both inhibitors and substrates of CYP3A4 and it has already been shown that drug levels are altered in the presence of other strong inhibitors or inducers of CYP3A4.^[15] Taken together, it can be assumed that the challenge of DDIs will certainly accompany HCV therapy in upcoming years, in particular, as combination treatments with several DAAs will most likely be necessary to finally achieve an efficient interferon-free anti-viral treatment.^{[6, 26]}

In summary, we have shown that DDIs in HCV patients are manageable, as only a minority of drugs may be unsuitable for co-administration. Still, the patients' drug charts need to be checked carefully, including self-medication, which is time-consuming and requires sufficient interaction studies provided by the pharmaceutical companies. Drug interaction websites can be regarded as an important tool to aid in the management of DDIs in clinical practice. We believe that continued support of these websites would be very useful.

References

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Source

 

The clinical importance of hepatitis C genotyping in the United States

By Scott O’Brien, November 2013

Hepatitis C virus (HCV) infection is the most common chronic blood-borne infection in the United States: nearly four million persons are chronically infected.¹ HCV infection is cleared in fewer than 20% of infected people, with the majority developing chronic HCV infection leading to increased risk of liver cirrhosis, hepatocellular carcinoma (HCC), liver failure, and related morbidities.¹ HCV-related morbidity and mortality is further driven by the estimates that, due to the asymptomatic nature of infection and slow disease progression, 45% to 85% of infected patients are unaware of their HCV infection until they present with liver disease.¹ Currently, there is no effective vaccine for HCV; clinical efforts are focused on prevention of infection, identification of infected individuals, and therapeutic treatment of infected individuals. Decisions to treat HCV-positive individuals are based upon the severity of the patient’s clinical features. The HCV genotype is used to aid in treatment decisions and determine the type of treatment, dosage, and duration of therapy, and to estimate the likelihood of response.^2-3

HCV-associated morbidity and mortality

Upon infection, some people note fatigue, loss of appetite, muscle aches, or fever. In most individuals, the immune system is unable to clear the infection and HCV chronic infection progresses over decades, which may lead to liver inflammation and elevated liver enzyme levels. An estimated 20% of individuals infected with HCV will progress to cirrhosis 20 years after infection.¹ Up to 5% of persons with chronic HCV infection per year will progress to advanced cirrhosis and die from HCV-associated liver disease.¹

HCV infection is the leading indication for liver transplant and accounts for 50% of hepatocellular carcinoma cases. Due to the slow progression of HCV disease, 73.4% of HCV related deaths occur in persons aged 45-64 years,¹ one to four decades after initial infection.

Screening and diagnosis of HCV infection

Traditionally, HCV testing has been recommended for individuals at high risk for HCV transmission. High risk for HCV transmission includes individuals who have participated in injection drug use, undergone chronic hemodialysis, or received blood transfusions or organ transplants before 1992 or clotting factor concentrates manufactured before 1987.³This risk-based testing strategy has had limited success in accurately diagnosing HCV-positive individuals, with 45% of persons with HCV reporting no known exposure risk.¹

In an effort to diagnose more HCV-positive individuals prior to development of liver disease, the U.S. Centers for Disease Control and Prevention (CDC) recently released new age-based HCV screening guidelines. The CDC study determined that the prevalence of anti-HCV antibodies, which indicate exposure, was highest among persons born during 1945-1965 (at 3.25%), roughly five times higher than adults born in other birth cohorts. Another CDC HCV surveillance study found that persons born between 1945 and 1965 accounted for 58.5% of those who were HCV antibody-positive and 67.2% of those who were HCV RNA-positive.⁴ The recent CDC birth cohort screening recommendation states that adults born between 1945 and 1965 should receive one-time testing for HCV, regardless of risk. In an independent review, the U.S. Preventive Services Task Force (USPSTF) also supports the recommendation for birth cohort screening to drive improved health outcomes. The benefits of amended HCV diagnosis guidelines are to identify more infections prior to the onset of liver disease and thus better enable accurate diagnosis of active chronic HCV infection.

Individuals who are screened for or suspected of having acute or chronic HCV should initially be tested for the presence of anti-HCV antibodies. A positive HCV antibody test should be followed with an HCV RNA test to confirm active HCV infection versus prior exposure to HCV. A person with a positive HCV antibody test, but who has a negative HCV RNA, should be considered negative for HCV infection.⁴

The recommendation for a diagnostic HCV RNA test is supported by a CDC HCV surveillance study, which found that half of reported HCV infections did not have a positive HCV RNA test.⁴ As a result, it was not possible to determine whether the reported HCV infection was an active or previously resolved infection.

The overall goal of the updated CDC recommendation is to improve awareness of HCV infection and drive improved healthcare outcomes. The adoption of birth cohort screening at the same compliance rate as colorectal screening recommendations could identify 400,000 new HCV-infected individuals in the next three years. The use of HCV RNA testing may also improve the accuracy of HCV diagnosis and lead to follow-up medical evaluation.

HCV treatment guidelines

Once diagnosis is confirmed with a nucleic acid HCV RNA test, treatment decisions are based on multiple factors, including the severity of liver disease, the presence of other health issues, patient readiness for treatment, and potential for treatment side effects. The goal of antiviral therapy is to achieve Sustained Virological Response (SVR), defined as undetected HCV virus 24 weeks after completion of therapy. The treatment regimen varies by HCV genotype (Table 1).

Table 1. Current HCV testing guidelines

Duration of treatment for genotype 1 and 4 is based on specific stopping rules related to early virologic response to therapy determined by RNA viral load drop during the first 4 to 24 weeks of therapy. Genotype 1 patients receive triple therapy with pegylated interferon (PEG-IFN), ribavirin (RBV), and one of the FDA-approved protease inhibitors. No formal therapy guidelines exist for genotype 5 and 6 patients, but the typical treatment regimen is PEG-IFN and RBV. Genotype 2 and 3 patients are typically given, and respond well to, PEG-IFN/RBV therapy, with SVR rates of approximately 70%.

The evolution of HCV treatment

HCV therapy in the early 1990s focused on stimulating the patient’s innate antiviral immune response with interferon (IFN) therapy. By the 2000s, therapy that included the nonspecific antiviral drug ribavirin in combination with IFN improved SVR rates in genotypes 1-3 two- to threefold.⁶

The first antivirals that specifically targeted HCV, direct acting antivirals (DAAs), were approved in 2011. Two hepatitis C DAAs approved in 2011 prevent viral replication by inhibiting HCV’s NS3/NS4 proteases required for hepatitis C virus protein processing. The approval of protease inhibitor DAAs for HCV genotype 1, used together with PEG-IFN and RBV, improved SVR rates from 30% to approximately 60% to 70% SVR.⁵ Some persons do not reach SVR due to emergence of HCV drug resistance mutations to the protease inhibitors. In particular, HCV genotype 1, subtype A is more prone to developing resistance mutations that can reduce SVR.⁷ Other potential targets for HCV DAAs include HCV’s RNA-dependent RNA polymerase (NS5B) and the viral cofactor protein NS5A, which is required for viral replication.

At present, there are more than 25 drug candidates in phase II or phase III clinical trials targeting HCV infection. Three of the leading drug candidates in phase III trials (Sofosbuvir, Faldaprevir, and Simeprevir), used in combination therapy with PEG-IFN plus RBV (P/R), show 80% to 90% SVR rates in individuals with HCV genotypes 1a/1b (Table 2). Sofosbuvir is being evaluated on multiple genotypes, which may lead to DAA treatment options for non-genotype 1 individuals. Triple DAA therapy with ABT-450/267/333 plus ritonavir is being evaluated without PEG-IFN to reduce adverse treatment side effects while still delivering ~90% SVR.⁸

Table 2. Investigational phase II/III HCV therapies⁸

Numerous DAA drug candidates are in late-stage trials, and some are currently under priority marketing review, which may lead to FDA approval of these drugs by 2014. Future combination DAA therapy trials are focused on shorter treatment course, activity to all HCV genotypes, and elimination of PEG-IFN and ribavirin from the therapy. Ultimately, if these goals are achieved, the results would be reduced side effects from therapy, reduced drug resistance, and simplified therapy regimens to improve patient compliance through the course of treatment. The rapid advances in DAA development and the large number of clinical trials will likely deliver 8-to-12 week therapy for all genotypes, with SVR rates exceeding 90%, in the coming years.

Importance of accurate HCV genotyping

Hepatitis C virus genotyping is currently used as an aid in determining dose and duration and estimating therapeutic response. Based on the current standard of care, it is critical for patients to receive an accurate genotype, particularly in the case of patients with HCV genotype 1, as they are eligible for combination therapy with FDA-approved protease inhibitors. While the standard of care does not require subtyping of genotype 1, there is significant evidence indicating HCV genotype 1a is more likely to develop drug resistance mutations than genotype 1b.⁷ As a result, accurate genotype 1a and 1b subtyping may contribute to clinical decisions, such as beginning therapy immediately or waiting for more effective DAA combination therapy in the near future. It is possible that some of the new DAAs will be approved with genotype-specific indications with variation in dosage or duration for treating specific genotypes.

It is estimated that 3% of the world’s population is chronically infected with HCV.⁶ In the United States, HCV is an increasing cause of morbidity and mortality and the leading indication for liver transplant. In the last few years the CDC has expanded HCV screening efforts and recommended a new HCV diagnostic algorithm to drive HCV awareness just as new HCV therapies are nearing FDA approval. Expanded screening efforts with early and accurate diagnosis and genotyping are now more important than ever as delivering an effective and accessible cure for HCV becomes a reality.

References

1. CDC. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR. 2012;61(RR-4).
2. CDC. Hepatitis C Information for Health Professionals.http://www.cdc.gov/hepatitis/hcv. Accessed September 28, 2013.
3. Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update.Hepatology. 2009;49(4):1335-1374.
4. CDC. Vital signs: evaluating of hepatitis C virus infection testing and reporting–eight U.S. sites, 2005-2011. MMWR. 2013;62(18).
5. Feld JJ, Shah H. Hepatology–management of hepatitis C infection.http://www.clinicaloptions.com/inPractice/Hepatology/Hepatology/ch8_Mgmt_of_Hep_C_Infection/Pages/Page%201.aspx. Accessed September 28, 2013.
6. Gaetano JN, Desai AP, Reau N. The era of direct-acting antivirals: The evolving role of interferon and ribavirin for the treatment of chronic hepatitis C. Clin Med Insights: Therapeutics. 2012:(4)39-56.
7. Cento V, Mirabelli P, Salpini R, et al. HCV genotypes are differently prone to the development of resistance to linear and macrocyclic protease inhibitors.http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0039652. Accessed September 28, 2013.
8. Muir AJ. HCV: Highlights from EASL 2013.http://www.chronicliverdisease.org/disease_focus/ppts/ch/HCV_Highlights_from_EASL_2013_Muir.pdf. Accessed September 28, 2013.

Source

Hepatitis C viral infection and the risk of dementia

Eur J Neurol. 2013 Dec 7. doi: 10.1111/ene.12317. [Epub ahead of print]

Chiu WC, Tsan YT, Tsai SL, Chang CJ, Wang JD, Chen PC; Health Data Analysis in Taiwan (hDATa) Research Group.

Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan; Department of Psychiatry, Cathay General Hospital, Taipei, Taiwan; School of Medicine, Fu Jen Catholic University, Taipei, Taiwan.

Abstract

BACKGROUND AND PURPOSE: Hepatitis C virus (HCV) infection may cause cognitive impairment, but no studies have focused specifically on cognitive impairment stemming from HCV. The purpose of this study was to investigate the potential increased risk for dementia in HCV-infected patients.

METHODS: A population-based cohort study based on the Taiwan National Health Insurance Research Database was conducted. From all potential participants aged 50 years or more, a total of 58 570 matched (1:1) pairs of HCV-infected patients and non-HCV-infected patients were included. Each subject was individually tracked from 1997 to 2009 to identify incident cases of dementia (onset in 1999 or later). Cox proportional hazards regressions were employed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between HCV infection and dementia.

RESULTS: There were 2989 dementia cases from the HCV-infected cohort during the follow-up period of 533 861.1 person-years; the overall incidence rates of dementia differed from the non-HCV cohort (56.0 vs. 47.7 cases per 10 000 person-years, P < 0.05). The adjusted HR for dementia was 1.36 (95% CI 1.27-1.42) for HCV-infected patients after adjusting for alcohol-related disease, liver cirrhosis, hepatic encephalopathy and hepatocellular carcinoma.

CONCLUSIONS: HCV infection may increase the risk for dementia. Further mechanistic research is needed.

© 2013 The Author(s) European Journal of Neurology © 2013 EFNS.

KEYWORDS: Alzheimer's disease, chronic hepatitis, dementia, hepatitis C

PMID: 24313931 [PubMed - as supplied by publisher]

Source

Under the watchful eye of ‘a benevolent dictator’

General practitioner and patient experiences of hepatitis C treatment initiation and shared-care in general practice

Australian Family Physician Volume 42, No.12, December 2013 Pages 900-903

Abstracr

Background

Innovative models of hepatitis C treatment delivery are needed to increase treatment uptake.

Methods

A qualitative evaluation of the Australasian Society for HIV Medicine’s Initiation of Hepatitis C Treatment in General Practice Pilot was conducted between November 2010 and June 2012. Structured interview schedules collected data on the treatment experiences of seven general practitioners (GPs) and eight of their patients.

Results

GPs were satisfied with the process of initiating hepatitis C treatment. They were generally positive about the support they had experienced under shared-care arrangements with tertiary clinics and they saw few barriers to initiating treatment. Similarly, patients appreciated the continuity of care that this treatment model affords, the convenience of accessing treatment from their GP and being treated by a GP they trusted.

Conclusion

The initiation of hepatitis C treatment through general practice is a viable model that could increase the number of people accessing hepatitis C treatment.

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Australia has up to 10 000 new hepatitis C infection notifications each year and an ageing population of affected people.¹ There is an increasing need for treatment to avoid the social and economic burdens associated with advanced liver disease.² Currently, the uptake of treatment in Australia is low, especially among people who inject drugs: only 2% of an estimated 217 000 people living with chronic infection are treated each year.³ Over the past decade innovative models of hepatitis C treatment delivery have been trialled in opiate-substitution treatment settings,⁴ general practice,⁵community health clinics^6,7 and via nurse-led outreach.⁸ The aim of diversifying models of treatment delivery is to increase treatment awareness, accessibility and uptake among affected populations.⁹

In an effort to expand the reach of hepatitis C treatment, the Australasian Society for HIV Medicine (ASHM) developed a pilot project of hepatitis C treatment initiation in general practice. The initiation pilot limited recruitment to patients with genotypes 2 or 3 because the duration of treatment is a relatively short 24 weeks and around 80% of patients with genotypes 2 and 3 can expect a sustained virological response (SVR).¹⁰ On the other hand, treatment for genotypes 1, 4, 5 and 6 is for 48 weeks; the SVR rates are significantly lower, at around 50%, and adverse events are more likely to occur because of the extended time patients spend in treatment.

By the time the pilot concluded in June 2012, 38 people with hepatitis C had been treated by eleven initiation prescribers from metropolitan and regional general practices throughout New South Wales. The initiation pilot connected general practitioners (GPs) with specialist physicians and shared-care teams of allied health professionals who treat hepatitis C patients in authorised tertiary liver clinics. Training of GPs during the pilot included a 2-day workshop with leading specialist physicians, presentations from positive-speakers and information modules. An evaluation of the pilot project explored GPs’ and patients’ experiences of treatment initiation in general practice. This article reports on findings from the evaluation regarding the criteria for and barriers to becoming an initiation prescriber, and the dynamics of shared-care.

Method

In 2009, the Highly Specialised Drugs Program gave approval for a 3-year pilot project for accredited community-based medical practitioners to initiate s100 antiviral therapy for chronic hepatitis C. ASHM developed and implemented a treatment initiation training program for GPs, and a qualitative evaluation of the ASHM initiation pilot was concomitantly conducted by the National Centre in HIV Social Research between September 2010 and November 2011. Two brief, structured interview schedules, each comprising nine open-ended questions, were used to explore seven GPs’ and eight patients’ experiences of the ASHM Initiation of Hepatitis C Treatment in General Practice Pilot. Telephone interviews with GPs and patients averaged 15–20 minutes each.

Participants: general practitioners and patients

Seven of a total of 11 GPs who participated in the initiation pilot were interviewed for this evaluation. All were long-term opioid-substitution treatment (OST) prescribers, and one GP was also a HIV-treatment prescriber. Four out of the seven GPs worked in community-based practices with high hepatitis C case loads. The GPs’ clinical roles included general health care, hepatitis C-specific health care, and initiation of hepatitis C treatment. These roles were in addition to the GPs’ involvement in OST. No specialist physicians were interviewed for this evaluation.

In addition, eight male hepatitis C patients with genotypes 2 or 3 volunteered to participate in the pilot. These men were recruited because they were patients of the GPs involved in the pilot and were interviewed 4–12 weeks after treatment initiation. The men were aged 38–53 years, four were unemployed and four worked, and all were either currently receiving OST or had received treatment in the past. This paper presents a descriptive content analysis of interview data collected during the initiation pilot.¹¹ This analytical approach highlighted the issues most often raised by participants during interviews.

Results

1. General practitioners in the initiation pilot project

a. Becoming an initiation prescriber

Participants identified several key criteria for becoming an initiation prescriber. First, it was believed necessary to have a good, trusting relationship with a specialist physician. Second, it is desirable to have previous experience of working in a shared-care environment. Finally, it is important to have prior experience of caring for people with hepatitis C.

‘[Y]ou know, if [a] GP who’s never seen a hep C patient before can start doing this stuff, I think you’re gonna get some curry floating around. You’re gonna get wrong doses. You’re gonna get patients, you know, sick with neutropenias.’ (GP 4)

Participants stated that a GP needs to have a reasonable case load of hepatitis C patients for the initiation training to be effectively applied. Two participants estimated that to become an initiation prescriber, a GP should care for a minimum of 5 patients all the way through treatment and have a minimum ongoing hepatitis C case load of 10 patients per year. Participants warned against underestimating the challenges of initiating and managing the regimen.

‘… I remember having some sort of scary moments along the way … I’d only caution most people to bear in mind that when they do carry the can that they might find that they’d want to have a little more experience behind them than they think.’ (GP 1)

A majority of participants reported high levels of satisfaction with the initiation training and saw no major barriers to applying the knowledge they had acquired. However, some had experienced a delay of several months between receiving the training and initiating treatment for their first patient. Similarly, the length of time some patients take to decide to have treatment, and then prepare for treatment, could delay applying the knowledge gained during the training.

‘The main barrier is getting patients treatment-ready, which takes a long time. It takes years, on the whole, for people to get around to getting treatment. So the time lags here are enormous.’ (GP 3)

Initiating hepatitis C treatments in a community-based practice requires access to adequate levels of psychosocial support for managing depression, anger and other psychiatric impacts of treatment among patients. Poor access to psychosocial support was reportedly a potential barrier to GP initiation of treatment.

‘[I]t’s quite hard sometimes to, to engage enough support. And that’s why there's a focus in the course on using peer support organisations and counselling services, and so on.’ (GP 6)

b. Shared-care: the pros and cons

The most satisfying aspects of shared-care, according to GPs who participated in this pilot, were: (i) the opportunity to network with health professionals who specialise in hepatitis C treatment; (ii) being mentored and supported by a specialist physician; and (iii) being part of a scientific milieu connected to clinical trials where innovation shaped clinical practice.

‘Well the thing that works best is the … access to information so that means that I’m able to give up-to-date information about hepatitis C treatment and outcomes … cause it’s a changing field … so I can tell people … “We can treat you. I can tell you what your outcome is likely to be” … ‘ (GP 3)

‘[H]aving a benevolent dictator at the top of the tree there, the collaborating specialist available, is useful.’ (GP 4)

However, developing a network of allied health professionals for shared-care was described as difficult and time-consuming. Similarly, there was a lack of stability in some shared-care arrangements because of ongoing changes to staffing at local hospitals; this had undermined the effectiveness of at least one team during the pilot.

‘So we had a great … dietician also and a social worker but … those services have been taken off us. We had a full-time nurse, now we’re down to a part-time nurse … So just constant changes is what’s incredibly frustrating for us at the moment … they’ve not been able to offer [our nurse] a full-time job so … she’s moved on … it just does interfere [with shared-care].’ (GP 2)

2. Patients in the initiation pilot

The eight patients whose treatment was initiated by their GP and who participated in the evaluation of the pilot had experienced symptoms from hepatitis C infection that had reduced their quality of life. The appeal of GP-initiated treatment for these patients centred on the benefits of continuity of care, where hepatitis C treatment was seen as an extension of health services already being provided by their GP. Other factors that attracted participants to GP-initiated treatment included a familiarity with practice staff, avoidance of stigma and discrimination, which participants perceived as more likely in tertiary health care settings, ready access to emotional support, and high levels of trust in their GPs.

‘Well I think the reason I took it up was … purely because my GP sort of assured me that, “If anything goes wrong, we’re there for you all the time.” So … I felt more comfortable.’ (Patient 7)

‘I think the GP is probably gonna understand your problems and stuff a lot, a lot more than some stranger in a hospital.’ (Patient 8)

The regulations surrounding the dispensing of hepatitis C treatment medications via the community pharmacy led to access difficulty for some participants who were required to travel long distances to reach major hospitals to fill their prescriptions. Despite this minor difficulty, GP-initiated treatment afforded greater convenience for participants as GPs were able to coordinate the ongoing testing and monitoring that is required during treatment. Participants valued the convenience, safety and personal care provided by their GPs and practice nurses.

‘… [My GP] has people to do the blood tests. You get to see your GP once a week also … and … the nurse, they explain [the results] to you. They ask you how you're feeling. They make you feel a lot more comfortable. And, since you’ve known them for a while, you do feel comfortable.’ (Patient 6)

All participants reported that the offer of treatment through their GP had been the primary motivating factor in deciding to commence treatment.

Discussion

All GPs who participated in the ASHM Initiation of Hepatitis C Treatment in General Practice Pilot reported a high level of satisfaction with the training they had received during the trial. The training for the pilot gave GPs the expertise and confidence to initiate hepatitis C treatments for patients with genotypes 2 and 3. Similarly, patient-participants in this pilot reported high levels of satisfaction regarding their experience of GP treatment initiation.

Becoming an initiation prescriber: criteria and barriers

As has been noted in previous research,¹² to meet the criteria for initiation prescribing, GPs need a sufficient hepatitis C case load to enable the knowledge and skills obtained during the training to be applied in a timely manner. While most GPs in the pilot project prescribed opioid-substitution treatments, worked in high case load practices and had expertise in providing psychosocial support for their patients, some had reported substantial time lags between their training and initiating their first patient, or they had few patients under their care who required treatment at the time of the pilot. Time delays and small case loads can potentially reduce GPs’ expertise and confidence in applying the training. Strategies such as evening seminars, workshops and other opportunities for professional development can be implemented to keep prescribers up to date. Another approach to keeping updated, and which was suggested by several GPs, is uploading the content of the training modules to the internet. It is likely, however, that many GPs who are interested in becoming hepatitis C treatment initiation prescribers will have sufficient case loads to sustain their skills.

The dynamics of shared-care

Currently, there is little evidence-based support in the literature for shared-care.¹³ Building stable and productive shared-care teams can be difficult and expensive because it involves complex, cross-system coordination of health care resources and staffing. Nonetheless some research has found that shared-care has contributed significantly to improving hepatitis C treatment adherence,¹⁴ including among people with psychiatric and substance use disorders.¹⁵Shared-care has also been described as an important asset for treating patients in regional areas¹⁶ and other community settings.¹⁷ Generally, GPs viewed shared-care in the pilot project as an opportunity to develop professional relationships with specialists and allied health professionals. In some instances during the pilot, suitable professional networks for shared-care were pre-existing; however, it often requires considerable time and effort to constitute shared-care teams.

It is likely that for GP-initiated hepatitis C treatment to work, GPs need to establish a strong relationship with a specialist, built on mutual respect and trust, or they risk being marginalised within shared-care arrangements. Conversely, the tertiary treatment centres have to embrace shared-care for treatment initiation in general practice to work. Notwithstanding these dynamics, the coordination of procedures, such as testing, and the communication of test results, which were integral to the success of shared-care, had generally worked well throughout the pilot.

Patient perspective

Most patient-participants in the pilot contrasted the relatively intimate model of GP-initiated treatment with their experience of large, impersonal hospital-based services. Patient-participants conceptualised GP-initiated treatment as a personable, safe, convenient and logical extension of their health service needs: many patient-participants had known their GPs for years, sometimes since childhood. They trusted their GP and they also had a good rapport with the general practice staff, including receptionists and practice nurses. GP participants knew their patients’ medical history and their drug use history, and participants felt no pressure to explain themselves or their past behaviour. The GPs were often managing participants’ OST, so having them also manage hepatitis C treatment was viewed as a natural continuation of this care – a one-stop-shop approach.^18,19 The patient-participants liked their GPs doing all the blood testing, because it was more convenient than attending a large hospital where people are more likely to be shunted between departments, and where they risk encountering hostile attitudes from unfamiliar hospital staff. Community-based practices are often closer to home than tertiary clinics, there is usually a wide choice of appointment times available, and it is possible to book appointments at short notice. Patient-participants wanted the opportunity to have hepatitis C treatment in a safe and familiar environment, which was convenient and well supported.

It should come as no surprise that people with a history of injecting drug use are enticed by the prospect of GP-initiated hepatitis C treatment. This model of treatment delivery circumvents a need to regularly attend large health care facilities, where stigmatisation of, and discrimination against, people with hepatitis C remains a considerable concern.²⁰

This article draws upon data from a qualitative evaluation of the ASHM’s Initiation of Hepatitis C Treatment in General Practice Pilot. Although the sample of GPs in this pilot was small, it comprised seven of the total of 11 GPs in NSW who participated in the pilot, which is approximately 64% of participating GPs. As patient-participants were interviewed before treatment concluded, no data on SVR rates were collected, so it was not possible to compare SVRs for GP-initiated treatment with SVRs from clinical trials or tertiary liver clinics. Finally, this evaluation did not include interviews with specialist physicians, so their views on all aspects of the pilot remain unknown. Future evaluations should record the experiences of specialist physicians.

Implications for general practice

• Hepatitis C treatment delivery through general practice can significantly increase the number of sites throughout Australia where people will be able to access hepatitis C treatment.
• GP-initiated treatment under a shared-care model encouraged hepatitis C patients to have treatment.
• The evidence presented in this article supports the initiation of hepatitis C treatment by GPs within a program of shared-care.
• Hepatitis C treatment initiation can enhance GPs’ clinical skills, increase the breadth of GPs’ professional networks and facilitate an ongoing therapeutic relationship between GPs and patients with hepatitis C, many of whom fear stigmatisation from health care services.

Competing interests: None.
Ethics approval: Ethics approval for the evaluation was obtained from the Royal Australian College of General Practitioners (reference number: NREEC 09-023).
Provenance and peer review: Not commissioned; externally peer reviewed.

Acknowledgements

The authors would like to thank the Centre for Social Research in Health (formerly the National Centre in HIV Social Research), which is supported by a grant from the Commonwealth Department of Health and Ageing. The Australasian Society for HIV Medicine funded the evaluation. Finally, we thank all GPs, their staff and patients who volunteered to participate in the evaluation.

References

1. The Kirby Institute. HIV, viral hepatitis and sexually transmissible infections in Australia: Annual Surveillance Report 2012. Sydney: The Kirby Institute for Infection and Immunity in Society, the University of New South Wales, 2012. Search PubMed

2. Australian Government Department of Health and Ageing. Third National Hepatitis C Strategy 2010–2013. Canberra: Commonwealth of Australia, 2010. Search PubMed

3. National Centre in HIV Epidemiology and Clinical Research. HIV/AIDS, viral hepatitis and sexually transmissible infections in Australia Annual Surveillance Report 2009. Sydney: National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, 2009. Search PubMed

4. Novick D, Kreek MJ. Critical issues in the treatment of hepatitis C virus infection in methadone maintenance patients. Addiction 2008;103:905–18. Search PubMed

5. Hellard M, Wang Y. The role of general practitioners in managing and treating hepatitis C. Med J Aust 2009;191:523–24. Search PubMed

6. Grebely J, Knight E, Genoway KA, et al. Optimizing assessment and treatment for hepatitis C virus infection in illicit drug users: a novel model incorporating multidisciplinary care and peer support. Eur J Gastroen Hepatol 2010;22:270–77. Search PubMed

7. Grebely J, Raffa J, Meagher C, et al. 2007b. Directly observed therapy for the treatment of hepatitis C virus infection in current and former injection drug users. J Gastroen Hepatol 2007b;22:1519–25. Search PubMed

8. Boonwaat L, Haber P, Levy M, et al. Establishment of a successful assessment and treatment service for Australian prison inmates with chronic hepatitis C. Med J Aust 2010;192:496–500. Search PubMed

9. Treloar C, Hull P, Bryant J, et al. Factors associated with hepatitis C knowledge among a sample of treatment naive people who inject drugs. Drug Alcohol Depend 2011;116:52–56. Search PubMed

10. Tarantino G, Craxi A. Optimizing the treatment of chronic hepatitis due to hepatitis C virus genotypes 2 and 3: a review. Liver Int 2009;29(s1):31–38. Search PubMed

11. Minichiello V, Aroni R, Timewell E, et al. In-depth interviewing: Principles, techniques, analysis. 2nd edn. Sydney: Longman, 2000. Search PubMed

12. Lambert SM, Page AN, Wittmann J, et al. General practitioner attitudes to prescribing hepatitis C antiviral therapy in a community setting. Aust J Prim Health 2011;17:282–87. Search PubMed

13. Smith SM, Allwright S, O’Dowd T. Effectiveness of shared care across the interface between primary and specialty care in chronic disease management [review]. Cochrane DB Syst Rev 2009; 3: doi:10.1002/14651858.CD004910.pub2. Search PubMed

14. Kontorinis N, Garas G, Young Y, et al. Outcome, tolerability and compliance of compassionate use interferon and ribavirin for hepatitis C infection in a shared care hospital clinic. Intern Med J 2003;33:500–04. Search PubMed

15. Ho SB, Groessl E, Dollarhide A, et al. Management of chronic hepatitis C in veterans: The potential of integrated care models. Am J Gastroenterol 2008;103:1810–23. Search PubMed

16. Ewart A, Harrison L, Joyner B, et al. Providing treatment for hepatitis C in an Australian district centre. Postgrad Med J 2004;80:180–82. Search PubMed

17. John-Baptiste A, Varenbut M, Lingley M, et al. Treatment of hepatitis C infection for current or former substance abusers in a community setting. J Viral Hepatitis 2009;16:557–67. Search PubMed

18. Treloar C, Newland J, Rance J, et al. Uptake and delivery of hepatitis C treatment in opiate substitution treatment: Perceptions of clients and health professionals. J Viral Hepatitis 2010;17:839–44. Search PubMed

19. Rance J, Newland J, Hopwood M, et al. The politics of place(ment): Problematising the provision of hepatitis C treatment within opiate substitution clinics. Soc Sci Med 2012;74:245–53. Search PubMed

20. Hopwood M, Treloar C, Bryant J. Hepatitis C and injecting-related discrimination in New South Wales, Australia. Drugs: Educ Prevent Policy 2006;13:61–75.  Search PubMed

Correspondence afp@racgp.org.au

Source

Hepatocarcinogenesis in CHC patients achieving a SVR to interferon: significance of lifelong periodic cancer screening for improving outcomes

J Gastroenterol. 2013 Dec 8. [Epub ahead of print]

Hepatocarcinogenesis in chronic hepatitis C patients achieving a sustained virological response to interferon: significance of lifelong periodic cancer screening for improving outcomes

Yamashita N, Ohho A, Yamasaki A, Kurokawa M, Kotoh K, Kajiwara E.

Department of Hepatology, Steel Memorial Yawata Hospital, 1-1-1 Harunomachi, Yahatahigashi-ku, Kitakyushu, 805-8508, Japan, naoyamgggg@gmail.com.

Abstract

BACKGROUND: Due to advances in interferon (IFN) therapy for chronic hepatitis C, most elderly patients, and even many of those with advanced hepatic fibrosis, now achieve a sustained virological response (SVR). However, carcinogenesis remains problematic in these patients. Hence, we aimed to elucidate risk factors for hepatocarcinogenesis in SVR patients and to present an appropriate follow-up protocol for improving outcomes.

METHODS: We retrospectively studied 562 consecutive SVR patients for a median observation period of 4.8 years.

RESULTS: Hepatocellular carcinoma was diagnosed in 31 patients (5.5 %). Respective cumulative incidences were 3.1, 10.1, and 15.9 % at 5, 10, and 15 years after completion of IFN therapy. The proportional hazards model identified moderate or advanced fibrosis stage, advanced age, habitual alcohol consumption, and alpha-fetoprotein elevation as determinants of carcinogenesis, with hazard ratios of 10.7 (p < 0.001), 4.1 (p < 0.01), 3.9 (p < 0.01), and 2.6 (p < 0.05), respectively. Carcinoma was diagnosed in 26 % of patients more than 10 years after completion of IFN therapy. Unexpectedly, F2 fibrosis was detected in 42 % of these patients. The 5-year survival rate was 93 % in the patients who had received periodic cancer screening but only 60 % in those who had not.

CONCLUSION: We recommend that SVR patients be observed at 6-month intervals, at a minimum, to facilitate diagnosis at an early stage, for as long as possible after completion of therapy even if not at an advanced stage of fibrosis.

PMID: 24317936 [PubMed - as supplied by publisher]

Source

The Metabolic Syndrome and Chronic Liver Disease

Curr Pharm Des. 2013 Dec 5. [Epub ahead of print]

Rosselli M, Lotersztajn S, Vizzutti F, Arena U, Pinzani M, Marra F.

Dipartimento di Medicina Sperimentale e Clinica Largo Brambilla, 3 I-50134 Florence, Italy. fabio.marra@unifi.it.

Abstract

The prevalence of the metabolic syndrome (MetS), a cluster of cardiovascular risk factors associated with obesity and insulin resistance, is dramatically increasing in Western and developing countries. This disorder is not only associated with a higher risk of appearance of type 2 diabetes and cardiovascular events, but impacts on the liver in different ways. Nonalcoholic fatty liver disease (NAFLD) is considerd the hepatic manifestation of the MetS, and is characterized by triglyceride accumulation and a variable degree of hepatic injury, inflammation, and repair. In the presence of significant hepatocellular injury and inflammation, the picture is defined 'steatohepatitis' (NASH), that has the potential to progress to advanced fibrosis and cirrhosis. Diagnosis of NASH is based on a liver biopsy, and active search for noninvasive tests is ongoing. Progression of steatohepatitis to advanced fibrosis or cirrhosis has been shown in at least one third of patients followed with paired biopsies. Presence of NASH is associated with lower life expectancy, both due to liver-related death and an increase in cardiovascular events. The appearance of NAFLD is mainly dependent on increased flow of fatty acids derived from an excess of lipolysis from insulin-resistant adipose tissue. Development of NASH is based on lipotoxicity and is influenced by signals derived from outside the liver and from intrahepatic activation of inflammatory and fibrogenic pathways. The presence of the MetS is also associated with worse outcomes in patients with cirrhosis due to any causes, and has complex interactions with hepatitis C virus infection. Moreover, the MetS poses a higher risk of development of hepatocellular carcinoma, not necessarily through the development of NASH-related cirrhosis. In conclusion, the presence of metabolic alterations has a severe and multifaceted impact on the liver, and is responsible for a higher risk of liver-dependent and -independent mortality.

PMID: 24320032 [PubMed - as supplied by publisher]

Source

The Discovery of Ledipasvir (GS-5885), a Potent Once-Daily Oral NS5A Inhibitor for the Treatment of Hepatitis C Virus Infection

John O. Link, James G. Taylor, Lianhong Xu, Michael L Mitchell, Hongyan Guo, Hongtao Liu, Darryl Kato, Thorsten Kirschberg, Jianyu Sun, Neil Squires, Jay Parrish, Terry Kellar, Zheng-Yu Yang, Chris Yang, Mike Matles, Yujin Wang, Kelly Wang, Guofeng Cheng, Yang Tian, Erik Mogalian, Elsa Mondou, Melanie Cornpropst, Jason Perry, and Manoj C. Desai

J. Med. Chem., Just Accepted Manuscript • Publication Date (Web): 09 Dec 2013

Downloaded from http://pubs.acs.org on December 11, 2013

Just Accepted

“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Discovery of Ledipasvir (GS-5885), a Potent Once-Daily Oral NS5A Inhibitor for the Treatment of Hepatitis C Virus Infection

John O. Link,*† James G. Taylor,† Lianhong Xu,† Michael Mitchell,† Hongyan Guo,† Hongtao Liu,† Darryl Kato,† Thorsten Kirschberg,† Jianyu Sun,† Neil Squires,† Jay Parrish,† Terry Keller,† Zheng-Yu Yang,† Chris Yang,‡ Mike Matles,‡ Yujin Wang,‡ Kelly Wang,‡ Guofeng Cheng,¥ Yang Tian,¥ Erik Mogalian,± Elsa Mondou,≠ Melanie Cornpropst, ≠ Jason Perry,÷ and Manoj C. Desai†

†Medicinal Chemistry, ‡Drug Metabolism, ¥Biology, ± Formulation and Process Development, ≠Clinical Research, ÷ Structural Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404

Abstract

A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 hours in healthy volunteers, and produces a rapid > 3 log10 viral load reduction in monotherapy at oral doses of 3 milligrams or greater with once-daily dosing in genotype 1a HCV infected patients. 39 has been shown to be safe and efficacious with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.

Introduction

Hepatitis C virus (HCV) infection is a significant public health concern with approximately 170 million infected individuals worldwide, and is the leading cause of liver transplant and hepatocellular carcinoma.1 HCV is the most common chronic blood-borne pathogen in the U.S., and the Center for Disease Control and the U.S. Preventative Services Task Force are aligned in recommending that all “babyboomers” (individuals born between 1945 and 1965) undergo testing for HCV infection.2 Until recently, the standard of care for treatment of genotype 1 (GT1) infection (60% of total infections worldwide among the seven known genotypes, with both GT1a and GT1b as major subtypes)3 consisted of weekly pegylated interferon (PEG) injections and twice daily oral ribavirin (RBV) for 24 or 48 weeks (duration based on response-guided therapy). PEG/RBV treatments achieve up to 54-63% sustained virologic response (SVR) in GT1 patients,4 but treatment is accompanied by considerable toxicity including flu-like symptoms, depression, and anemia.5 Tripletherapy containing PEG/RBV combined with three times daily dosing of the recently approved direct-acting antiviral (DAA) protease inhibitor telaprevir or boceprevir has improved the GT1 HCV SVR rates to 66-79% for treatment naïve patients, but with increased toxicities including rash (telaprevir) or grade 3/4 anemia.6 Prior null responders (patients who attained less than a 1 log viral load reduction on PEG/RBV) are not indicated for retreatment with PEG/RBV due to SVR rates <10%, with minimal improvement to 29% for patients undergoing triple-therapy.7 Finally, a growing number of patients are identified as interferon intolerant or unwilling to take interferon. PEG-free therapy is necessary to serve a broader patient population, improve outcomes, and provide a safer, simpler regimen.8

We have sought to identify safe oral drugs for combination treatment of HCV infection. In addition to programs targeting the NS3 protease,9 NS5B polymerase (both nucleotides10 and non-nucleotides11), we initiated an NS5A inhibitor program with the goal of identifying an agent with characteristics that would allow its use in combination with DAAs having complementary mechanisms to achieve high SVR rates with a short treatment duration.

Despite significant study, the mechanistic role of NS5A in the HCV life-cycle remains enigmatic.12 NS5A has no known enzymatic activity, and has no homologs in prokaryotes or eukaryotes. Nonetheless, the protein is critical for HCV viability; in clinical monotherapy studies NS5A inhibitors produce the most rapid viral load declines of any HCV antiviral class. It has been postulated that this rapid decline in HCV RNA is based on inhibition of viral replication (as with NS3 and NS5B inhibitors), and additional inhibition of virion assembly or secretion from infected cells.13

Early NS5A inhibitors were found empirically through screening of the GT1b replicon. Several series of lipophilic proline, proline-mimetic, or alanine-amide inhibitors of the GT1b replicon had been discovered (1-3, Figure 1),14 but these inhibitors typically have ~1000 fold weaker activity against the GT1a replicon.15 A polyaromatic pyridopyrimidine class (4) affords nanomolar activity against both GT1a and 1b replicons.16 Dimeric series provide potent GT1b-active stilbene diamide inhibitors (5 discovered from monomer series 1),17 and highly potent GT1a and 1b active bis-imidazole biphenyl inhibitors including daclatasvir 6 (BMS-790052, GT1a EC50 = 50 pM), which achieved clinical proof-of-concept for the NS5A mechanism.18 NS5A has emerged as an important drug target for the treatment of HCV infection.19

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Chronic hepatitis virus infection increases the risk of pancreatic cancer: a meta-analysis

Hepatobiliary Pancreat Dis Int. 2013 Dec;12(6):575-83.

Xing S, Li ZW, Tian YF, Zhang LM, Li MQ, Zhou P.

Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Health, and Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China. pzhou@tjh.tjmu.edu.cn.

Abstract

BACKGROUND: Several reports have inconsistently demonstrated that there is an association between hepatitis B virus (HBV) or hepatitis Cvirus (HCV) infections and pancreatic cancer (PC). The aim of the present meta-analysis is to assess this possible relationship.

DATA SOURCES: Studies were identified by searching available database from January 2000 to July 2012. Possible associations between PC risk and hepatitis B surface antigen (HBsAg) and its antibody (HBsAb), hepatitis B e antigen (HBeAg) and its antibody (HBeAb), anti-HBcAg antibody (HBcAb), and HCV antibody (anti-HCV) were evaluated.

RESULTS: Eight case-control and two cohort studies were included, and their quality scores were assessed by the modified Newcastle-Ottawa Quality Assessment Scale (NOS). We found that HBsAg and anti-HCV seropositivity significantly increased risk of PC (OR=1.28, 95% CI: 1.11-1.48 and OR=1.21, 95% CI: 1.02-1.44). The presence of HBsAb was associated with a statistically significant decrease in the risk of PC (OR=0.40, 95% CI: 0.20-0.79) and HBeAb (OR=0.62, 95% CI: 0.39-0.99). HBsAg-/HBcAb+/HBsAb- or HBsAg-/HBcAb+/HBsAb+ profile was not related to PC risk (OR=1.57, 95% CI: 0.83-2.98 and OR=1.24, 95% CI: 0.72-2.14).

CONCLUSIONS: HBV/HCV infection increases the risk of PC. HBsAb and HBeAb seropositivity may be the protective factors against PC. It is still uncertain whether serological pattern of past exposure to HBV with or without natural immunity is associated with an enhanced probability of this malignancy.

PMID: 24322741 [PubMed - in process]

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