Medical innovation and ethical dilemmas are intertwined in gastroenterology and hepatology. This narrative review explores direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) as a touchstone example of how medical innovation breeds ethical dilemmas. A few quandaries-informed consent as well as informed deferral during the first wave of DAA approvals, sobriety restrictions from payors, and high DAA costs for patients-are addressed through the lens of the foundational principles of clinical medical ethics: autonomy, beneficence, non-maleficence, justice, and utility. By placing these issues within a medical ethics framework, we hope not only to focus on the solutions that the gastroenterology and hepatology community developed in the advent of DAA therapy, but to highlight an ethical paradigm that can be applied to similar dilemmas that will be faced as new therapies for other gastrointestinal diseases are approved.

Safe and efficacious pan-genotypic direct-acting antiviral (DAA) regimens, such as sofosbuvir and daclatasvir (SOF + DCV), facilitate simplified models of care for hepatitis C virus (HCV). However, in Cambodia access to HCV testing and treatment has typically been low. In response, Médecins Sans Frontières (MSF) implemented a HCV testing and treatment pilot project in Phnom Penh, Cambodia in 2016. This project provides the first real-world evidence of SOF + DCV effectiveness across a large patient cohort using a simplified care model in Cambodia. Patients treated with SOF + DCV from September 2016 to June 2019 were included in the analysis. Medical standard operational procedures (SOPs) were simplified significantly across the study period. Treatment effectiveness was assessed by sustained viral response at 12 weeks post-treatment (SVR12) according to a modified intention-to-treat methodology. Treatment safety was assessed by clinical outcome and occurrence of serious and nonserious adverse events (S/AE). Of 9158 patients, median age was 57 years and 39.6% were male. At baseline assessment, 27.2% of patients had compensated cirrhosis and 2.9% had decompensated cirrhosis. Genotype 6 was predominant (53.0%). Among patients analysed according to modified intention to treat (n = 8525), treatment effectiveness was high, with 97.2% of patients achieving SVR12. Occurrence of SAE was low (0.7%). Treatment effectiveness and safety was not affected by the iterative simplification to treatment modality. In conclusion, in this large treatment cohort in Phnom Penh, Cambodia, the SOF + DCV regimen showed high rates of treatment effectiveness and safety across patient sub-groups and during progressive simplification.

There is an urgent need to increase patient access to treatment of chronic hepatitis C virus (HCV) infection. We developed a colocalized HCV clinic integrated within a primary care practice. We report the prevalence of HCV and evaluate the impact of the integrated clinic on the HCV cascade of care.

We performed a retrospective study of patients with chronic HCV infection from 2 clinic practices, an integrated clinic practice and a similar nonintegrated clinic practice, between July 2015 and July 2016. Demographic, clinical, and HCV testing data were reviewed to estimate the prevalence of chronic HCV and to construct a cascade of care.

A total of 8405 primary care patients were included; 4796 (57.1%) received an HCV antibody test and 390 (8.1%) were positive. A total of 310 patients with chronic HCV were included in the analysis. There were 119 patients eligible for linkage to care in the nonintegrated clinic, of which 80 (67.2%) were referred, 38 (31.9%) were linked, and 18 (15.1%) initiated treatment during the study period. Among the 70 patients eligible for linkage to care in the integrated clinic practice, 51 (72.9%) were referred, 38 (54.3%) were linked, and 16 (22.9%) initiated treatment. In a multivariable analysis, patients in the integrated clinic practice had significantly higher odds of being linked to care than patients in the nonintegrated clinic practice (adjusted odds ratio [OR] 2.5, 95% confidence interval [CI] = 1.3-4.8).

We found a high seroprevalence of chronic HCV within our clinic population and demonstrate that a HCV clinic integrated into a primary care center increases linkage to care for patients with chronic HCV.

From 2010, the landscape of hepatitis C therapeutics has been changed rapidly, and today we are standing at a cusp of a pharmacological revolution where highly effective and interferon (IFN)-free direct acting antivirals (DAAs) are already on the market. Such treatment paradigms attain 90-95% sustained virologic response (SVR; undetectable viral load at week 12 or 24 at the end of therapy) rates in treated individuals compared to 50-70% with treatment completion of dual-therapy-pegylated interferon (PEG-IFN) and ribavirin (RBV). As the major goal now for the hepatologists, clinicians, physicians, and health care workers is likely to eradicate hepatitis C infection in parallel to treatment, the demand is for a one-size-fits-all pill that could be prescribed beyond the limitations of hepatitis C genotype, viral load, previous treatment history, advanced hepatic manifestations (fibrosis, cirrhosis) and antiviral drug resistance. Although the new treatment strategies have shown high cure rates in clinical trials, such treatment paradigms are posing dilemmas too in real-world clinical practice. Therapy cost, treatment access to low and middle-income countries, treatment-emergent adverse events, lack of effective viral screening and disease progression simulation models are potential challenges in this prospect. This review article deeply overviews the challenges encountered while surmounting the burden of hepatitis C around the world.

Boceprevir was not previously studied with peginterferon alfa-2a/ribavirin in phase III trials in treatment-naïve chronic hepatitis C patients. The international phase IIIb/IV TriCo study was, therefore, designed to evaluate boceprevir in combination with peginterferon alfa-2a/ribavirin in treatment-naïve genotype 1 patients.

A total of 165 treatment-naïve genotype 1 patients were assigned to boceprevir plus peginterferon alfa-2a/ribavirin therapy according to the label. All patients received a 4-week lead-in with peginterferon alfa-2a/ribavirin, after which boceprevir (2400 mg/day) was introduced. The total duration of treatment ranged from 28 to 48 weeks depending on the virological response at Weeks 4, 8, and 24, and on fibrosis status. The primary efficacy outcome was sustained virological response (SVR) [undetectable hepatitis C virus (HCV) ribonucleic acid (RNA) 12 weeks after actual end of treatment, SVR12].

The overall SVR12 rate was 81% (133/165, 95% confidence interval 74-86%). After 8 weeks of treatment, 61% of patients had undetectable HCV RNA, and 78 patients (47%) had an early response (undetectable HCV RNA at Weeks 8 and 24) and were eligible to stop all therapy at Week 28. Among early responders the SVR12 rate was 95% (74/78), and among patients with cirrhosis assigned to 48 weeks' treatment, the SVR12 rate was 67% (14/21). The overall relapse rate was 7% (10/143), and was 4% (3/77) among early responders. The most common adverse events were anemia (41%), neutropenia (32%), and dysgeusia (31%).

High SVR12 rates can be achieved with boceprevir plus peginterferon alfa-2a/ribavirin in treatment-naïve HCV genotype 1 patients, including patients with well-compensated cirrhosis. Treatment is well tolerated when label restrictions are taken into account.

ClinicalTrials.gov Identifier: NCT01591460.

F. Hoffmann-La Roche Ltd.

The first liver transplantation (LT) was performed by Thomas E Starzl five decades ago, and yet it remains the only therapeutic option offering gold standard treatment for end-stage liver disease (ESLD) and acute liver failure (ALF) and certain early-stage liver tumors. Post-liver transplantation survival has also dramatically improved over the last few decades despite increasing donor and recipient age and more frequent use of marginal organs to overcome the organ shortage. Currently, the overall 1 year survival following LT in the United States is reported as 85 to 90%, while the 10 years survival rate is ~50% (http://www.unos.org). The improvements are mainly due to progress in surgical techniques, postoperative intensive care, and the advent of new immunosuppressive agents. There are a number of factors that influence the outcomes prior to transplantation. Since 2002, the model for end-stage liver disease (MELD) score has been considered a predicting variable. It has been used to prioritize patients on the transplant waiting list and is currently the standard method used to assess severity in all etiologies of cirrhosis. Hepatocellular carcinoma (HCC) is the most common standard MELD exception because the MELD does not necessarily reflect the medical urgency of patients with HCC. The criteria for candidates with HCC for receiving LT have evolved over the past decade. Now, patients with HCC who do not meet the traditional Milan (MC) or UCSF criteria for LT often undergo downstaging therapy I an effort to shrink the tumor size. The shortage of donor organs is a universal problem. In some countries, the development of a deceased organ donation program has been prevented due to socioeconomic, cultural, legal and other factors. Due to the shortage of cadaveric donors, several innovative techniques have been developed to expand the organ donor pool, such as split liver grafts, marginal- or extended-criteria donors, live donor liver transplantation (LDLT), and the use of organs donated after cardiac death. Herein, we briefly summarize recent advances in knowledge related to LT. We also report common causes of death after liver transplant, including the recurrence of hepatitis C virus (HCV) and its management, and coronary artery disease (CAD), including the role of the cardiac calcium score in identifying occult CAD.

Dogan S, Gurakar A. Liver Transplantation Update: 2014. Euroasian J Hepato-Gastroenterol 2015;5(2):98-106.

Despite the development of potent antiviral drugs, HCV remains a global health problem; global eradication is a long way off. In this review, we discuss the immune response to HCV infection and particularly, the interplay between viral strategies that delay the onset of antiviral responses and host strategies that limit or even eradicate infected cells but also contribute to pathogenesis. Although HCV can disable some cellular virus-sensing machinery, IFN-stimulated antiviral genes are induced in the infected liver. Whereas epitope evolution contributes to escape from T cell-mediated immunity, chronic high antigen load may also blunt the T cell response by activating exhaustion or tolerance mechanisms. The evasive maneuvers of HCV limit sterilizing humoral immunity through rapid evolution of decoy epitopes, epitope masking, stimulation of interfering antibodies, lipid shielding, and cell-to-cell spread. Whereas the majority of HCV infections progress to chronic hepatitis with persistent viremia, at least 20% of patients spontaneously clear the infection. Most of these are protected from reinfection, suggesting that protective immunity to HCV exists and that a prophylactic vaccine may be an achievable goal. It is therefore important that we understand the correlates of protective immunity and mechanisms of viral persistence.

High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen.

In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy.

The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events.

Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.).

Elucidation of the natural history of chronic hepatitis C (CHC) and the identification of risk factors for its progression to advanced liver disease have allowed many physicians to recommend deferral treatment (triple therapy) in favour of waiting for new drug availability for patients who are at low risk of progression to significant liver disease. Newer generation drugs are currently under development, and are expected to feature improved efficacy and safety profiles, as well as less complex and shorter duration delivery regimens, compared to the current standards of care. In addition, patients with cirrhosis and prior null responders have a low rate (around 15%) of achieving sustained virological response (SVR) with triple therapy, and physicians must also consider the decision to wait for new treatments in the future for these patients as well. Naïve patients are the most likely to achieve a close to 100% SVR rate; therefore, it may be advisable to recommend that patients with mild to moderate CHC should wait for the newer therapy options. In contrast, patients with advanced fibrosis and cirrhosis will be those with the greatest need for expedited therapeutic intervention. There remains a need, however, for establishing definitive clinical management guidelines to maximize the benefit of waiting for new drugs and minimize risk of side effects and non-response to the current triple therapy.