Wednesday, March 1, 2017

Hepatitis C drugs re-energize global fight over patents

Hepatitis C drugs re-energize global fight over patents
Lawsuits in India and Argentina seek to reduce drug costs by allowing generic versions of antiviral treatments.
Amy Maxmen
The liver disease hepatitis C is the new battleground for lawsuits intended to slash the cost of life-saving medicines. In February alone, five suits were filed in India and Argentina claiming that the latest class of antiviral drugs does not warrant the 20-year patent monopoly that manufacturers have sought in those countries.

In the 2000s, successful challenges to patents on HIV drugs gave poor nations access to high-quality ‘generic’ copies of the medications at rock-bottom prices. Now, buoyed by that success, activists are applying the same strategy to a fresh wave of hepatitis C drugs. They note that the standard 12-week course of treatment costs more than the average annual salary for millions of people in middle-income countries.
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Developing a new algorithm to diagnose advanced liver fibrosis: A lift or a nudge in the right direction?

Developing a new algorithm to diagnose advanced liver fibrosis: A lift or a nudge in the right direction?
Leon A. Adams, Richard K. Sterlinga
DOI: http://dx.doi.org/10.1016/j.jhep.2017.02.011

Publication stage: In Press Accepted Manuscript
Published online: February 17, 2017

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Accurate identification of liver disease severity and fibrosis stage is paramount in the management of those with chronic liver disease. In the past, this was often done by liver biopsy. However, due to it’s invasiveness and risks of bleeding, pain, and sampling error, non-invasive assessment of liver disease has gained increasing attention over the last decade. Non-invasive tests can be divided into serum tests and imaging tests. Although standard “liver function” tests, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are inaccurate when used alone, several models have been developed that use them in combination with other markers of advanced liver disease, such as platelet count. Of those models that utilize routine, readily available tests, the AST-Platelet Ratio Index (APRI) and FIB-4 have gained the most attention[[1], [2]]. Both APRI and FIB-4 have high specificity and negative predictive value’s (NPV) for advanced fibrosis or cirrhosis[[1], [2]]. However, both have only moderate positive predictive values (PPV) and many patients fall in between the upper and lower cut-offs giving an indeterminate result. More complex serum panels have been developed including Fibrosure/Fibrotest[3] and Fibrometer[4], which may offer additional accuracy compared to APRI or FIB-4 but have extra cost. In addition, the alternative non-invasive imaging tests, such as vibration controlled transient elastrography (VCTE)[5] or magnetic resonance elastrography (MRE)[6] are generally only available in specialized centers, leaving many with chronic liver disease inadequately assessed. Because one serum or imaging test alone does not provide 100% sensitivity and specificity, there has been an attempt to combine tests, either performed together or sequentially[[4], [7], [8], [9], [10], [11], [12], [13], [14], [15]]. Thus, the rationale for the study by Boursier and colleagues published in the current issue of the Journal of Hepatology was to develop such a test as part of an algorithm to more accurately and easily identify advanced liver disease[16].

To that goal, the study aimed to develop and validate a stepwise algorithm that could be easily used by all providers to facilitate detection of advanced fibrosis in those with chronic liver disease. The cohort studied consisted of 3754 subjects with chronic liver disease who had undergone liver biopsy and VCTE, who were divided 2:1 into a derivation and validation set. They initially evaluated the utility of both APRI and FIB-4 as an initial screening test. Because FIB-4 outperformed APRI (higher sensitivity), they used it to compare to their new “first line test” which included age, gender, gamma-GT (GGT), AST, platelet count, and prothrombin time (PT). Each of these variables was assigned a number (0-4 depending on the variable and cut off) in the “easy LIver Fibrosis Test (eLIFT), with a score of at least 8 providing 80% sensitivity for advanced fibrosis. In a core group of 1946 subjects, they found that while FIB-4 and eLIFT had similar sensitivity (77-78%), eLIFT had higher specificity (91%), NPV (79%), and PPV (91%) with fewer false positive results than FIB-4, especially in those over age 60. They concluded that eLIFT was better than FIB-4 as a general screening test.

Subsequently, they determined what should be the “second line test” by comparing APRI, FIB-4, liver stiffness by VCTE, and Fibrometer (with or without VCTE) and found that FibrometerVCTE had the highest number of biopsies avoided (81%). A new algorithm was proposed with eLIFT as the initial screening test followed by FibrometerVCTE in those with an eLIFT score ≥ 8 for confirmation. Using this two-step strategy, 46% of patients (33% with eLIFT score <8 and 14% with eLIFT ≥ 8 but FibrometerVCTE <0.384) would not need to see a specialist thus avoiding liver biopsy or additional testing. This two-step approach found that 34% had advanced fibrosis (eLIFT >8 and FibrometerVCTE ≥ 0.715) leaving only 19% with an indeterminate result that might go on to liver biopsy. This combined strategy worked better than FIB-4 or FibrometerVCTE alone in identifying those with advanced fibrosis. Finally, they followed 1275 patients longitudinally (median follow-up 2.9 years) to determine if the eLIFT-FibrometerVCTE strategy could predict liver-related and all-cause mortality. Although eLIFT and FIB-4 had similar performance for all-cause mortality, FibrometerVCTE had the best performance for predicting liver-related mortality.

This study has several strengths; the large patient population enabled comparison of several methods of fibrosis assessment and detected relatively small differences in test performance. Furthermore, the proposed algorithm was accurate across a wide spectrum liver disease increasing applicability and attractiveness to implement in the community. In addition, eLIFT and FibrometerVCTE were demonstrated to be prognostic of liver related outcomes, re-enforcing the appropriateness to use them as tests to guide patient management. Nevertheless, the eLIFT test utilizes some serum tests that may not be routinely ordered by community physicians, such as prothrombin time, which in itself may suffer inter-laboratory variability. In addition, the use of AST and GGT in the eLIFT algorithm, resulted in a reduction in specificity in the setting of alcoholic liver disease. Nevertheless, this was resolved when combined with the FibrometerVCTE. The FibrometerVCTE was developed using the M probe, which provides higher values than the XL probe and has a lower success rate in obesity, limiting applicability in this population. For these reasons, independent validation will be important to confirm the accuracy of the eLIFT-FMVCTE algorithm. Lastly, the study population was not identified from the general population, and so caution should be exercised in trying to extrapolate this algorithm to screen for fibrosis in the general population.

 Combining non-invasive algorithms is an attractive way of increasing diagnostic accuracy for liver fibrosis, however uncertainty exists on the best way to combine tests and which tests to use. For example, tests may be used concurrently with discordant results leading to a diagnostic biopsy. Alternatively two modalities may be combined into one diagnostic formula, or thirdly, tests may be used sequentially, with the first being a screening test and the second used following an indeterminate screen or as a confirmatory test for a positive screening test. The approach by Boursier utilizes a combination of firstly, a two-step approach using eLIFT as a screening test and FibrometerVCTE as the confirmatory test, which in itself combines VCTE and a serum test[16]. Thus, this approach requires three non-invasive tests to be performed, adding to the complexity and cost.

In addition to the current study, a range of alternative combination strategies have been examined (outlined in Table 1), primarily among patients with chronic hepatitis C (CHC)[[7], [8], [9], [14], [15], [16], [17], [18], [19]]. These have included the SAFE algorithm which sequentially combines APRI and Fibrotest[8], sequential APRI and Hepascore[13], concurrent Fibrotest and Fibroscan[14] and combining Fibrometer and Fibroscan into one diagnostic model[15]. In non-alcoholic fatty liver disease, concurrent Fibroscan and NAFLD Fibrosis Score and sequential FIB4 and BARD have been proposed[[7], [12]], whilst in chronic hepatitis B, a combination of concurrent ALT with Fibroscan followed by the Enhanced Liver Fibrosis Score or the Forns index has been examined[[9], [10]] Overall, these studies demonstrate an increase in diagnostic accuracy and higher predictive values with multiple non-invasive tests compared with single tests, particularly for the determination of moderate degrees of fibrosis (e.g. METAVIR F2+).

Table 1Cross-sectional studies (n>200) examining the accuracy of combination non-invasive fibrosis tests in the prediction of advanced fibrosis or cirrhosis.
AuthornLiver DiseaseOutcomeAlgorithmsDiagnostic AccuracySensitivitySpecificityNPVPPV
Boursier 2009332MixedCirrhosisAPRI → Fibrotest80%44%93%81%71%
Fibrotest + Fibroscan94%89%96%96%90%
Fibrometer / Fibroscan91%75%97%91%91%
Sebastiani 20092035HCVCirrhosisAPRI → Fibrotest92%90%93%56%99%
Castera 2010302HCVCirrhosisAPRI → Fibrotest89%86%90%94%78%
Fibrotest + Fibroscan96%89%98%96%95%
Sebastiani 20121013HCVCirrhosisAPRI → Fibrotest91%82%92%98%57%
APRI + Fibrotest.94%73%97%96%73%
Boursier 20121785⁎HCVCirrhosisAPRI → Fibrotest89%61%93%95%56%
Fibrotest + Fibroscan94%86%95%98%76%
Fibrometer / Fibroscan87%----
Crisan 2012446HCVAdvanced fibrosisAPRI + FIB4 + Fibrometer89%84%91%94%76%
APRI + FIB4 + Fibrotest85%88%83%95%68%
APRI + FIB4 + Fibroscan86%62%100%59%100%
Wong 2014323HBVAdvanced fibrosisFibroscan + ELF-65-66%86-92%79-80%76-85%
Petta 2014321NAFLDAdvanced fibrosisFibroscan + FIB4-42-85%97-100%91-98%71-100%
Fibroscan + NFS-25-83%100%93-99%100%
FIB4 + NFS-14-35%100%88-91%100%
Boursier 20171946MixedAdvanced fibrosiseLIFT → Fibrometer/Fibroscan-78%91%79%91%

Fibroscan available in 729 patients. Mixed liver disease included patients with liver disease realted to alcohol, hepatitis c virus (HCV), hepatitis B virus (HBV), non-alcoholic fatty liver disease (NAFLD) and other causes. “→” indicates sequentially performed tests, “+” indicates concurrent tests, “/” indicates combined tests into one formula, ELF=Enhanced Liver Fibrosis score, APRI= AST to platelet ratio index.

Determining the optimal combination of tests is difficult as studies have been performed in different diseases, used different cut-offs and aimed to predict different stages of fibrosis. Notably, the only independent prospective multi-center evaluation of a range of non-invasive fibrosis tests including Fibrotest, Fibrometer, Hepascore, APRI and Fibroscan, found no difference in percentage of well-classified patients or biopsies avoided between synchronous combinations of the above tests, for the prediction of cirrhosis in patients with CHC[11]. However, other studies have found the combination of Fibroscan and a serum test (Fibrotest) is more accurate than the combination of two sequential serum tests incorporated into the SAFE algorithm (APRI and Fibrotest)[[14], [15]]. Using a serum based test in combination with elastography is an appealing strategy as they assess different pathophysiological properties associated with fibrosis, and thus this is currently suggested by EASL Guidelines[20]. However, the requirement for a concurrent Fibroscan limits the applicability of this strategy into the community. The ideal algorithm to screen the general population should be a combination of an inexpensive, accessible and highly sensitive test to minimize missed diagnoses, followed by a highly specific test to confirm the diagnosis. To this end, the eLIFT cut-off of eight was chosen to aim for 80% sensitivity, which translated to up to one third of patients with advanced fibrosis being missed but only 3-4% of cirrhotics. One option to minimize false negative cases would be to lower the eLIFT threshold, however this would be at the cost of a greater false positive rate and needless referral for further assessment. Other potential screening tests include FIB4 and APRI in combination given their wide-spread availability and low cost followed by elastrography in those with discordant or increased results above the lower threshold.

Because one test is often inadequate to answer both questions: which patient has minimal liver disease (F0-1) and secondly, which patient has advanced fibrosis (F3-4), it is clear that non-invasive fibrosis markers should not be used in isolation but incorporated into clinical acumen, imaging and other biochemical tests. Overall accuracy and predictive values are improved if two non-invasive fibrosis assessments are used. A sensitive, easy to perform screening test is required for community practitioners (e.g. serum test). More expensive and accurate confirmatory tests such as complex serum models or elastography, can then be done in the hepatology clinic. Currently, further independent comparisons are required to determine the optimal algorithms, however this will also be influenced by factors such including expense and availability. Of equal importance however, is the need to change the paradigm of liver disease assessment in the community to include fibrosis algorithms rather than relying on standard liver enzymes. Until then the current study is a nudge in the right direction.

http://www.journal-of-hepatology.eu/article/S0168-8278(17)30106-X/fulltext
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Hepatitis C - Real-life data on potential drug-drug interactions in patients undergoing interferon-free DAAs

Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study
Loreta A. Kondili , Giovanni Battista Gaeta, Donatella Ieluzzi, Anna Linda Zignego, Monica Monti, Andrea Gori, Alessandro Soria, Giovanni Raimondo, Roberto Filomia, Alfredo Di Leo, Andrea Iannone, Marco Massari, Romina Corsini,
Published: February 28, 2017

Abstract
Background
There are few real-life data on the potential drug-drug interactions (DDIs) between anti-HCV direct-acting antivirals (DAAs) and the comedications used.

Aim
To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study.

Methods
Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (www.hep-druginteractions.org).

Results
Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate-to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI.

Conclusions
Based on these results, we can estimate that 30–44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate-to-severe liver disease. For several drugs, the recommendation related to the DDI changes from “dose adjustment/closer monitoring”, in mild to moderate liver disease, to “the use is contraindicated” in severe liver disease.

Discussion Only

Polypharmacy has become an important issue among patients with HCV mono-infection, and DDIs are one of the challenges in the DAA-based treatment of these patients [9,10]. The most frequently reported drug interactions modify drug metabolism by inducing or inhibiting the cytochrome P450, leading to abnormal drug exposure [10].

Many of the DDI studies have been performed in healthy volunteers, yet HCV-infected patients with cirrhosis may have impaired CYP450 capacity and higher plasma concentrations of CYP450 substrates compared to healthy individuals. This would mean that they are at even more risk for drug toxicity when a DDI occurs. In light of this, different profiles of potential drug-drug interactions have been hypothesized in patients with moderate-to-severe liver disease, however, few data are available for real-life patients [11–13].

Our real-life data stress that potential DDIs are an important clinical issue for individuals treated with DAAs for chronic HCV infection. We found that a wide variety of drugs belonging to different classes were used, even wider than that reported by Siederdissen et al. [6], who conducted a single center survey and whose patients were around 10 years younger, presumably with fewer comorbidities than those in our cohort.

The profile of the patients in our study mirrored the epidemiology of HCV infection in Italy, whose prevalence is greatest among the elderly [14]. As a consequence, in our cohort, polypharmacy was relatively common in patients with mild liver disease as in those with moderate-to-severe liver disease. Of the patients with mild liver disease, 30% reported a potential Category 2 DDI, for which the most suitable approach is monitoring for the early detection of adverse events [6,15]. These data indicate that in patients with mild liver disease, through careful pre-treatment assessment of concomitant medications and monitoring or dose-modifications, significant DDIs can be avoided even in elderly patients who generally take multiple comedications for different comorbidities [10,16–19]. However, the use of contraindicated comedications (Category 3 of DDI) should always be checked and, if present, an alternative comedication should be provided, regardless of the severity of liver impairment. Our data showed that none of the patients with mild liver disease were taking contraindicated comedications during DAA treatment, whereas 10% of the comedications were contraindicated in patients with moderate-to-severe liver disease. Patients with moderate-to-severe liver disease were a group of particular interest, due to the intersection between older age, comorbidities and severity of liver disease. In this study, 44% of patients with severe liver disease were affected by more than one DDI. Of these patients, 17% used comedications that are contraindicated in cases of severe liver damage, mainly because of the possible deterioration of liver disease. That these drugs were prescribed and the lack of important clinical outcomes during ongoing DAA therapy could be explained by the fact that all were classified with Child-Pugh A liver cirrhosis, which indicated that the liver impairment was not very severe. However, clinicians should be aware of the possible interactions reported for different comedications and DAAs, in particular in patients with severe liver impairment [20].

Our series showed that DAA regimens containing a protease inhibitor (3D combination with ritonavir or SOF/SIM) was associated with a higher risk for DDIs (38% and 32%, respectively), compared to other SOF-containing regimens (11–23%). Furthermore, these regimens were contraindicated in patients with advanced/decompensated liver cirrhosis. The mechanism of DDIs in patients receiving the 3D regimen can primarily be attributed to the ritonavir component of 3D, whose mechanism of action is to modify the metabolism of concomitant drugs, mainly increasing concomitant drug concentrations [16].

Warnings on the administration of comedications with the DAA regimens that include protease inhibitors (3D and Simeprevir regimens) were released in 2015, when our data were being collected, which, over time, may have increased the awareness of possible DDIs related to these regimens [15,21,22].

In general, regimens with the NS5B inhibitor sofosbuvir plus an HCV NS5A inhibitor (i.e., ledipasvir, daclatasvir), which do not affect CYP450, were relatively free of significant pharmacokinetic interactions, even in patients with moderate to severe liver impairment.
PPIs were the most frequently used comedication in our study (used in 19% and 34% of patients with mild and moderate-to-severe liver disease, respectively). The possible DDIs between PPIs and DAAs has been emphasized recently, given that gastric pH could affect DAA bioavailability due to increased or decreased pharmacokinetics, as reported for 3D and SOF/LDV and in other DAA regimens containing NS3/4A protease inhibitors, such as grazoprevir, and the NS5A inhibitor elbasvir [23–26]. However, the finding of a post-hoc analysis provides reassurance that the co-administration of 3D and PPI does not negatively affect the chance of viral eradication [27].
In conclusion, hundreds of thousands of patients are currently being treated with DAAs, and, based on our real-life data, 30–44% of those taking comedications are at risk of a DDI. For several drugs, the recommendation related to a potential DDI depends on the severity of liver disease, and a careful evaluation of DDIs is required, particularly in patients with severe liver impairment. This stresses the need for increased awareness of this issue and for additional extensive research.

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