No one size fits all—Shortening duration of therapy with direct‐acting antivirals for hepatitis C genotype 1 infection

The advent of shorter duration, highly effective and well‐tolerated interferon‐free therapy now provides an opportunity for virtually all HCV‐infected individuals to be cured. However, there continues to be a need to simplify and shorten treatment duration. Shortening therapy to 8 weeks with sofosbuvir and ledipasvir can be considered in treatment patients with HCV genotype 1 infection and low baseline viral load. A number of other 8‐week dual and triple therapy direct‐acting antiviral (DAA) regimens are in advanced clinical development. Several small studies have further demonstrated the feasibility of 6 weeks of sofosbuvir therapy in combination with an NS5A inhibitor and a protease inhibitor for HCV genotype 1. Four weeks of therapy with various combinations of the currently available DAAs appears to be suboptimal with poor response rates observed in phase 2 trials. Response‐guided therapy is another promising tool that may allow for shorter therapy but require further research. Shortening therapy and retreating relapsers may be a viable cost‐saving measure, but requires further cost‐benefit analysis and more data on the impact of resistance on retreatment options.     

Response‐guided therapy in patients with genotype 1 hepatitis C virus: Current status and future prospects

On‐treatment responses to antiviral therapy are used to determine duration of therapy in patients being treated for genotype 1 hepatitis C virus infection. Such use of response‐guided therapy has successfully reduced exposure of patients to the side‐effects of pegylated interferon and ribavirin without jeopardizing overall treatment success. Response‐guided therapy is an integral part of treatment using the current standard treatments involving the direct‐acting antiviral (DAA) agents—boceprevir or telaprevir—combined with pegylated interferon/ribavirin. Improvements in our understanding of the kinetics of viral load during antiviral therapy have shown us that more potent suppression of viral replication increases the rate of viral eradication, providing impetus for the development of more potent DAAs. Emerging results from clinical trials of these agents—including trials of interferon‐free DAA combinations—suggest that very high rates of viral eradication are achievable, even in patients who failed to respond to previous courses of interferon‐based therapy. Furthermore, because of these high rates of treatment success, on‐treatment assessment of viral response may become unnecessary. The field of hepatitis C virus therapy is evolving rapidly and current trends indicate that the era of simple treatment regimens with high rates of success and good tolerability are near.     

Current prospects for interferon‐free treatment of hepatitis C in 2012

Present interferon‐based therapy for chronic hepatitis C is limited by both efficacy and tolerability. Telaprevir and boceprevir are the first two direct‐acting antiviral drugs (DAAs) that inhibit hepatitis C virus replication to be licensed for use in conjunction with pegylated interferon and ribavirin. Numerous other DAAs are in clinical development, and phases 2 and 3 trials are evaluating interferon‐free combination DAA therapy. Interferon‐free sustained virologic responses have now been achieved with combinations of asunaprevir and daclatasvir; sofosbuvir and ribavirin; sofosbuvir and daclatasvir; faldaprevir and BI207127; ABT‐450, ritonovir and ABT‐333; ABT‐450, ritonovir and ABT‐072; miracitabine, danoprevir and ritonavir; and alisporivir and ribavirin. Some drugs are genotype‐specific in their activity, whereas others are pan‐genotypic, and differential responses for the genotype 1 subtypes 1a and 1b have emerged with many DAA combinations. Viral breakthrough and resistance are important considerations for future trial design. The prospect of interferon‐free combination DAA therapy for hepatitis C virus is now finally becoming a reality.     

Pan‐genotypic treatment regimens for hepatitis C virus: Advantages and disadvantages in high‐ and low‐income regions

During the last 5 years, the availability of direct‐acting antiviral (DAA) agents has revolutionized the treatment of hepatitis C virus (HCV). Compared with interferon/ribavirin—the previous standard of care—DAA combination regimens offer improved sustained virological response (SVR) rates, shorter treatment durations of 8‐24 weeks, convenient once‐daily single‐tablet formulations and more favourable tolerability profiles. HCV treatment is complex, and the choice of therapy must consider a complex range of factors, including baseline viral load, fibrosis stage, the HCV genotype and subgenotype, and the presence of resistance‐associated substitutions at baseline. Globally, HCV genotype 1 predominates, and there are extensive data and various treatment options available for this genotype. Genotypes 2–6 are prevalent and may even predominate in different geographical regions, reflecting diverse factors including human migration patterns and unsafe use of injection drugs and blood products. Such factors are themselves influenced by socio‐economic factors, and poor regions often have the greatest unmet need for effective HCV therapies. The latest pan‐genotypic DAA combination regimens provide the potential to eradicate HCV around the globe, regardless of genotype, hence minimizing the need for virological testing services, which often are unavailable in poorer regions. Economics inevitably remain a barrier to access, and extensive cooperation will be required between clinical organisations and pharmaceutical manufacturers to agree appropriate pricing policies, especially in poorer economic regions. This review considers key data and treatment guidelines for DAA therapies, including pan‐genotypic combination regimens, in the context of regional differences in HCV genotype and socio‐economic factors.     

Therapy for hepatitis C genotype 3: moving forward

Until recently, the standard of care for hepatitis C virus genotype 3 infection was response‐guided therapy with pegylated interferon plus ribavirin for 16 to 48 or 72 weeks. The introduction of sofosbuvir plus ribavirin has revolutionized hepatitis C virus therapy. Nowadays, the recommend treatment regimen is a combination of sofosbuvir and a weight‐based ribavirin dose for 24 weeks. For easy to treat patients (e.g. naïve or previously treated patients without cirrhosis), this combination achieves high sustained virologic response rates and is well tolerated. However, in treatment‐experienced patients with cirrhosis, sustained virologic response is lower due to unknown reasons. The combination of two direct‐acting antiviral agents, sofosbuvir and daclatasvir, for 12 weeks is also associated with low sustained virologic response rates in this special population, for whom new drugs and different strategies are now under evaluation. Currently, the high cost of all these drugs limits access to treatment in many countries.     

Safety of Direct‐Acting Antiviral Therapy for Renal Function in Post‐Kidney Transplant Patients Infected with Hepatitis C Virus and a 100% 12‐Week Sustained Virologic Response: A Single‐Center Study

Treatment of chronic hepatitis C infection after renal transplantation has been controversial due to the high rate of graft rejections with interferon (IFN)‐based therapies. The aim of this study is to review our experience of direct acting antiviral therapy for the recipients of renal transplantation. Eleven recipients who were hepatitis C virus‐polymerase chain reaction (PCR) positive were eligible for the treatment with direct acting antivirals. Six recipients were treated with sofosbuvir and ledipasvir, three were treated with elbasvir and grazoprevir, and one was treated with sofosbuvir and ribavirin for 12 weeks. One recipient was treated with glecaprevir and pibrentasvir for 8 weeks. All of the 11 recipients exhibited sustained virologic response at week 12 after the end of treatment. Adverse events were scarce including the two recipients who switched to tacrolimus from cyclosporine at the beginning of the treatment. The direct acting antiviral therapy including new agents appears to be safe and highly efficacious for the recipients after renal transplantation.     

Hepatitis C virus genotype 4: Genotype 1's little brother

Treatment for hepatitis C virus genotype 4 infection has undergone a major advance over the past 5 years with the emergence of direct‐acting antiviral agents. Previously, genotype 4 treatment had been limited to the combination of pegylated interferon and ribavirin, with low rates of sustained virological response. The combinations of new direct‐acting agents have resulted in a radical improvement in hepatitis C therapy. Much of the currently available efficacy and safety information in the treatment of genotype 4 has been extrapolated through the results of genotype 1. In this report, we review the efficacy and safety data obtained in recent studies focusing on genotype 4 patients, including special populations, such as those with decompensated cirrhosis.     

Cost‐effectiveness of sofosbuvir for the treatment of chronic hepatitis C‐infected patients

The efficacy of treatment for hepatitis C genotype 1 infection has significantly improved with the introduction of first‐generation protease inhibitors. However, there remains a need for effective treatments for patients infected with other genotypes, for nonresponders and patients unsuitable for interferon. Sofosbuvir is the first nucleotide polymerase inhibitor with pan‐genotypic activity. Sofosbuvir‐based regimens have resulted in >90% sustained virological response across treatment‐naïve genotype 1–6 patients in five phase III clinical trials of sofosbuvir administered with ribavirin or pegylated interferon and ribavirin. This analysis evaluates the cost‐effectiveness of sofosbuvir within the current licensed indication, for genotype 1–6 in the UK. A Markov model followed a cohort of 10 000 patients over lifetime, with approximately 20% initiating treatment for compensated cirrhosis. Sofosbuvir‐regimens were compared to telaprevir, boceprevir, pegylated interferon and ribavirin, or no treatment. Costs and outcomes were discounted at 3.5%. The cost perspective utilized costs applicable to the National Health Service in the UK. Sofosbuvir proved to be cost‐effective in most patient populations with incremental cost‐effectiveness ratios (ICERs) at £11 836/QALY and £7292/QALY against telaprevir and boceprevir, respectively. In genotype 3, sofosbuvir had a weighted ICER of £18 761/QALY. Sofosbuvir‐based regimens are a cost‐effective option for the majority of hepatitis C‐infected patients in the United Kingdom although the incremental cost‐effectiveness varies by genotype and regimen. Sofosbuvir and ribavirin is an alternative regimen for patients unsuitable for interferon.     

Safety and efficacy of sofosbuvir‐based direct‐acting antiviral regimens for hepatitis C virus genotypes 1‐4 and 6 in Myanmar: Real‐world experience

This open‐label, clinical experience investigated the safety and efficacy of direct‐acting antiviral (DAA) hepatitis C virus (HCV) therapy in Myanmar; 344 patients completed treatment between June 2015 and May 2016. Patients with HCV genotypes 1‐4 and 6 received one of four treatments: (i) Peg‐interferon (PEG‐IFN)+sofosbuvir (SOF)+ribavirin (RBV) for 12 weeks, (ii) SOF+RBV for 24 weeks, (iii) ledipasvir (LDV)+SOF for 12 weeks or (iv) daclatasvir (DCV)+SOF+RBV for 12 or 24 weeks. Genotype 3 was most common (n=133, 38.7%), followed by genotype 6 (n=122, 35.5%) and genotype 1 (n=86, 25%). Overall, 91% of patients achieved sustained virologic response (SVR); 99% in group 1, (n=148/149), 90% in group 2 (n=95/106), 78% in group 3 (n=65/83) and 100% in group 4 (n=6/6). In group 3, SVR rates were 96.8% in genotype 1 (n=30/31) and 64.1% in genotype 6 (n=25/39). Multivariable regression analysis identified advanced fibrosis (F3‐4) (OR=.16 CI: 0.05‐0.57, P=.005), genotype 6 (OR=.35, CI: 0.16‐0.79, P=.012) and diabetes (OR=.29, CI: 0.12‐0.71, P=.007) as negative independent predictors of response. Adverse events were mild with all‐oral therapy. Conclusion: DAA therapy ±PEG‐IFN achieved high SVR rates. Genotype 6 patients had a low SVR to 12 weeks of LDV and SOF raising the need for other regimens, RBV or longer treatment duration in this population.     

Hepatitis C treatment from “response‐guided” to “resource‐guided” therapy in the transition era from interferon‐containing to interferon‐free regimens

Peginterferon/ribavirin has been the standard‐of‐care for chronic hepatitis C virus (HCV) infections: 48 weeks for genotype 1 or 4 (HCV‐1/4) and 24 weeks for HCV‐2/3. Response‐guided therapy recommended shorter 24‐ and 16‐week regimens for HCV‐1 with lower baseline viral loads (< 400 000–800 000 IU/mL) and rapid virological response (RVR, undetectable HCV RNA at week 4) and HCV‐2/3 with RVR, respectively; and extending to 72 and 48 weeks for HCV‐1 slower responders and HCV‐2 non‐RVR patients, respectively, to improve the efficacy. The progress of directly acting antivirals (DAA), moving from interferon‐containing regimens in 2011 to interferon‐free regimens in 2013, has greatly improved the treatment success. Interferon‐containing regimens include boceprevir or telaprevir or simeprevir or daclatasvir plus peginterferon/ribavirin, 24–48 weeks, for HCV‐1 or 4. However, adding these DAA has no benefit for HCV‐1 with lower baseline viral loads/RVR. Instead, 12‐week sofosbuvir plus peginterferon/ribavirin attained sustained virological response rates of > 90% for HCV‐1/3–6. Interferon‐free regimens include two main categories: NS5B nucleotide inhibitor (sofosbuvir)‐based regimens and NS3/4A inhibitor/NS5A inhibitor‐based regimens (daclatasvir/asunaprevir, paritaprevir/r/ombitasvir/dasabuvir and grazoprevir/elbasvir). About 8–24 weeks interferon‐free regimens could achieve sustained virological response rates of 82–99% for corresponding HCV genotypes. Although the newly DAA interferon‐free regimens have high efficacy and safety, the huge budget impact increases the treatment barriers. The current recommendation should, therefore, base on the availability, indication, and cost‐effectiveness in the transition era of DAA. Based on the concept of “resource‐guided therapy,” peginterferon/ribavirin might be applied for easy‐to‐treat interferon‐eligible patients in resource‐constrained areas. Prioritizing patients for interferon‐free regimens according to “time‐degenerative factors” (age and fibrosis) is justified before the regimens becoming available and affordable.     

Secondary prophylaxis of hepatocellular carcinoma: the comparison of direct‐acting antivirals with pegylated interferon and untreated cohort

During the past two decades, several studies showed reduced rates of hepatocellular carcinoma recurrence in patients with HCV‐related cirrhosis after interferon‐based antiviral therapies respect to untreated controls, even without reaching viral clearance. The recent development of new all‐oral regimens with direct‐acting antivirals has radically improved the therapeutic management of hepatitis C. Nevertheless, paradoxical, or at least unexpected, high rates of both occurrence and recurrence of hepatocellular carcinoma after a treatment with direct‐acting antivirals, have been reported in the recent literature. These findings generated a strong rebound in the hepatology community and are at present still controversial. We sought to compare the hepatocellular carcinoma recurrence‐free survival of a historical cohort treated with pegylated interferon/ribavirin and an untreated cohort with a cohort treated with direct‐acting antivirals.     

Interferon‐α/β for treatment of chronic hepatitis C infection in the era of direct‐acting antiviral agents

Type I interferons (IFN‐α/β), with or without ribavirin, have been the only agents that can eradicate the hepatitis C virus (HCV). An IFN‐free regimen combining oral direct‐acting antiviral agents (DAA) will be approved soon for genotype 1 patients. Here, we discuss the role of IFN‐α/β in the forthcoming “era of DAA” with consideration of limitations and concerns about IFN‐free therapies. First, the therapeutic efficacy of first‐generation DAA varies among the different subtypes. While the rate of sustained virological response (SVR) is 60–90% among patients with genotype 1b, the rate often falls short of 50% in patients with genotype 1a. IFN and ribavirin can still be indicated for patients with genotype 1a as a platform for combination with DAA. Second, there is concern about the emergence of drug‐resistance resulting from inappropriate use of DAA. The clinical significance of pre‐existing resistant variants has not been elucidated. Drug resistance may affect the efficacy of next‐generation treatments. An IFN and ribavirin backbone in combination with DAA is an effective measure to prevent the emergence of drug resistance and/or to suppress pre‐existing resistant viruses. Third, it remains unknown whether the incidence of hepatocellular carcinoma (HCC) will be reduced in patients who achieve SVR with IFN‐free regimens. In contrast, there are many reports in Japan demonstrating the preventive effects of IFN on the development of HCC. When patients do not achieve SVR with first‐generation DAA, low‐dose IFN maintenance therapy is a treatment option until the next‐generation therapy with pan‐genotypic potency and high genetic barrier become available.     

Chronic hepatitis C treatment in HIV co‐infection in Portugal: Results from a cohort OF 2133 patients presented by GEPCOI (Portuguese Coinfection Study Group)

Direct‐acting antiviral drugs (DAAs) have recently changed the paradigm of hepatitis C therapy, significantly improving treatment response rates, patient life expectancy and quality of life. In Portugal, sofosbuvir (SOF) and SOF/ledipasvir (SOF/LDV) were fully reimbursed by the National Health System since early 2015 and generalized use of interferon‐free DAA based regimens became current practice. During 2016, the remaining DAAs were sequentially added and covered by the same health access policy. The Portuguese Study Group of Hepatitis and HIV Co‐infection (GEPCOI) collected data from 15 clinical centres in Portugal, pertaining to the HCV treatment experience with DAA regimens. A cohort of 2133 patients was analysed, representing one of the largest DAA treated HCV/HIV co‐infected individuals. The global sustained virologic response (SVR) achieved was 95% in this real‐life cohort setting. Linear regression analysis showed significant differences in treatment response rates when using SOF plus ribavirin (RBV) combination in genotype 2 or 3 infected individuals (P < .002) and in those with liver cirrhosis (P < .002). These findings corroborate that early treatment is mandatory in HIV/HCV co‐infected patients, as response rates may be negatively influenced by higher fibrosis stages and suboptimal DAA regimens. The current national Portuguese health policy should continue to promote wider treatment access and individualized therapy strategies, aiming at the elimination of HCV infection in this high‐risk co‐infected population.     

Chronic hepatitis C and chronic kidney disease: Advances,limitations and unchartered territories

Over the past few years, treatment options for chronic hepatitis C virus (HCV) infection have evolved dramatically. The current approved interferon‐free direct‐acting antiviral (DAA) regimens have been shown to be safe and effective with sustained virologic response (SVR) rates of >90% in most patients. Unique issues yet remain such as the challenges in patients with impaired renal function or decompensated cirrhosis. Patients with stages 4‐5 chronic kidney disease (CKD) have a higher prevalence of HCV infection compared with the general population. Chronic HCV in those on dialysis and in kidney transplant recipients is associated with higher morbidity and mortality than uninfected patients. The HCV‐infected population is also at risk of developing extrahepatic manifestations associated with altered immune system function and chronic inflammation with cryoglobulinaemic vasculitis being the most common of these manifestations. Therefore, patients with CKD stages 4‐5 have to be considered priority patients for HCV therapy. New antiviral therapies have the potential to improve outcomes in this vulnerable patient population, including those on haemodialysis. Recently published studies conducted in kidney transplant recipients have demonstrated successful outcomes. It is thus essential that we carefully select the most appropriate DAA regimen and the best time for treatment in the context of kidney transplantation or cryoglobulinaemic vasculitis. While sofosbuvir, the only approved nucleotide NS5B inhibitor, has been the backbone of most pangenotypic therapeutic regimens, it has a limitation in those with advanced kidney disease. The currently approved regimens for those with stage 4/5 CKD, while effective, have challenges in that they apply to genotype 1/4 and may require RBV for genotype 1a. Globally, genotype 3 is a common infection, and thus, this group with CKD presents a huge unmet need for effective therapies. As therapy of HCV in renal transplant recipients has been highly successful, it provides an opportunity to expand the use of HCV‐infected organs in solid organ transplantation.     

HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy

Sustained virological response (SVR) rates have increased dramatically following the approval of direct acting antiviral (DAA) therapies. While individual DAAs have a low barrier to resistance, most patients can be successfully treated using DAA combination therapy. However, DAAs are vulnerable to drug resistance, and resistance-associated variants (RAVs) may occur naturally prior to DAA therapy or may emerge following drug exposure. While most RAVs are quickly lost in the absence of DAAs, compensatory mutations may reinforce fitness. However, the presence of RAVs does not necessarily preclude successful treatment. Although developments in hepatitis C virus (HCV) therapy in Asia have largely paralleled those in the United States, Japan’s July 2014 approval of asunaprevir plus daclatasvir combination therapy as the first all-oral interferon-free therapy was not repeated in the United States. Instead, two different combination therapies were approved: sofosbuvir/ledipasvir and paritaprevir/ritonavir/ombitasvir/dasabuvir. This divergence in treatment approaches may lead to differences in resistance challenges faced by Japan and the US. However, the recent approval of sofosbuvir plus ledipasvir in Japan and the recent submissions of petitions for approval of paritaprevir/ritonavir plus ombitasvir suggest a trend towards a new consensus on emerging DAA regimens.     

Sofosbuvir and ABT-450: Terminator of hepatitis C virus?

Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with this regimen. SVR rates are approximately 80% in patients with hepatitis C virus (HCV) genotype 2, 3, 5 and 6 and 40%-50% in patients with genotype 1 and 4. Therefore, strategies to improve SVR rates have been an important issue for clinical physicians. Several direct acting antiviral agents (DAAs) have significantly higher SVR rates when combined with pegIFN-α and RBV than pegIFN-α and RBV alone. Treatments containing DAAs have several advantages over the previous SOC, including higher specificity and efficacy, shorter treatment durations, fewer side effects, and oral administration. Based on these advantages, treatment with pegIFN-α and RBV plus telaprevir or boceprevir has become the current SOC for patients with genotype 1 HCV infection. However, many patients are either not eligible for therapy or decline treatment due to coexisting relative or absolute contraindications as well as an inability to tolerate the hematological side effects and adverse events caused by the new SOC. These factors have contributed to the advent of pegIFN-α-free regimens. The newest therapeutic regimens containing sofosbuvir and ABT-450 have shown promising results. In this review, we summarize the development of anti-HCV agents and the clinical efficacy of sofosbuvir and ABT-450-based therapies as well as the potential for future HCV studies.     

The influence of immunosuppressants on direct‐acting antiviral therapy is dependent on the hepatitis C virus genotype

Background

Direct‐acting antivirals (DAAs) have substantially increased sustained virological response rates after liver transplantation, with improved tolerance compared to interferon‐based therapy. The influence of immunosuppressive agents on the efficacy of DAAs has not been clarified.

Methods

Subgenomic hepatitis C virus (HCV) replicons for genotype (GT) 1b, 2b, 3a, and 4a were treated with the mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus or with the calcineurin inhibitors (CNIs) cyclosporine or tacrolimus, either alone or in combination with selected DAAs. Cell proliferation‐related effects were excluded with MTT assays. HCV replication activity was quantified by quantitative real‐time polymerase chain reaction or luciferase assay.

Results

Addition of either mTOR inhibitor to the DAA daclatasvir (DAC) resulted in a 30% increase in antiviral activity compared to DAC alone for HCV GT2a, GT3a, and GT4a (all P ≤ .01). Similar results were obtained using sofosbuvir and ledipasvir. In contrast, addition of either mTOR inhibitor to DAC induced a 30% reduction in antiviral activity in GT1b cells (P ≤ .01 vs DAC alone). Neither CNI affects the antiviral activity of the DAAs in any HCV GT.

Conclusion

For patients with HCV GT2a, GT3a, or GT4a infection, mTOR‐based immunosuppressive therapy may be beneficial. CNI‐based therapy may be more efficacious in GT1b patients, as mTOR inhibitors seem to impair antiviral efficacy of DAAs in HCV GT1b infection.     

Interferon‐free therapies for patients with chronic hepatitis C genotype 3 infection: A systematic review

Treatment of hepatitis C virus (HCV) infection with genotype 3 remains a challenge. The HCV elimination rate with direct‐acting antivirals (DAAs) is lower than the values reported for other HCV genotypes. In addition, genotype 3‐infected patients have a higher risk of disease progression and hepatocellular carcinoma. The aim of this study was to review the relevant literature concerning the treatment of HCV genotype 3 patients with interferon‐free regimens. A literature search was conducted in the PubMed/Medline, Embase and Web of Science electronic databases. Trials enrolling patients with chronic hepatitis C infection treated with DAAs with or without ribavirin were included. Two investigators independently evaluated the trials for inclusion criteria, risk of bias and data extraction. The primary outcome was sustained virological response (SVR). In total, 323 references were identified, and 29 met the inclusion criteria: 18 general clinical trials, three general observational studies, three studies in patients with decompensated liver cirrhosis and four studies in HIV–HCV‐coinfected patients. Overall, 4068 genotype 3 patients were included. As compared with sofosbuvir and ribavirin for 24 weeks, sofosbuvir/velpatasvir for 12 weeks or sofosbuvir plus daclatasvir plus ribavirin for 12 weeks provided higher SVR rates, particularly in patients with cirrhosis. Treatment of patients with decompensated cirrhosis remains a great challenge. Sofosbuvir/ledipasvir+ribavirin for 12 weeks were associated with an SVR of 85% in these patients. In summary, treatment of HCV genotype 3 patients is improving rapidly, and this population may no longer be considered a difficult‐to‐treat subgroup in the near future.     

Real‐world experiences with direct‐acting antiviral agents for chronic hepatitis C treatment

As direct‐acting antiviral (DAA) agents become more readily available for the treatment of chronic hepatitis C, it is important to understand real‐world treatment experiences. In order to assess the effectiveness of DAA regimens and factors that influence sustained virologic response (SVR) rates in the Veterans Affairs healthcare system, we retrospectively identified veterans with chronic hepatitis C who were treated with DAAs from January 2014 to June 2015. We determined SVR rates and collected data on demographics, genotype (GT), previous interferon‐based treatment, antiviral regimens, and co‐morbidities (HIV, prior solid organ transplant, haemodialysis) for analysis. Of 15 720 veterans, the majority were infected with genotype 1a (GT1a, 60.5%). Excluding the special populations, the overall cohort SVR rate was 92%. Compared to treatment‐experienced patients, treatment‐naïve patients had significantly higher SVR rates (90% vs 92%, P = .006). Subgroups associated with lower likelihood of achieving SVR‐included African Americans (OR 0.79, 95% CI 0.69‐0.91), GT3 (OR 0.65, CI 0.50‐0.86), and cirrhosis (OR 0.91, CI 0.84‐0.99) or decompensated cirrhosis (ascites: OR 0.78, CI 0.67‐0.91, variceal bleed: OR 0.75, CI 0.57‐0.99). The only treatment regimen independently associated with lower SVR rates was SOF+RBV+IFN (OR 0.65, CI 0.50‐0.84). Special populations achieved high SVR rates: HIV 92%, haemodialysis 93%, liver transplant 96% and renal transplant 94%. In conclusion, overall SVR rates were comparable to those reported in clinical trials and carried over to historically more difficult‐to‐treat patients. Several patient‐ and treatment‐related factors were identified as independent predictors of treatment failure and suggest subgroups to target for efforts to improve therapeutic strategies.     

Add‐on effects of fluvastatin in simeprevir/pegylated‐interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study

Background

The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated‐interferon (Peg‐IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct‐acting antiviral‐containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add‐on treatment in Peg‐IFN and RBV combination therapy for HCV‐infected patients significantly improved the sustained virologic response (SVR), but the add‐on effect of FLV on SMV combination therapy is not well understood.

Methods

This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b‐infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12 weeks of SMV/Peg‐IFN/RBV followed by 12 weeks of Peg‐IFN/RBV with or without 24 weeks of FLV. The SVR rate and adverse events were compared between the two groups.

Results

Thirty‐one patients were allocated to the FLV add‐on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis‐4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end‐of‐treatment response rates, SVR rates at 24 weeks after treatment, and safety profiles were also similar between the two groups.

Conclusions

This prospective, randomized, multicenter study indicated that FLV had no add‐on effect when given with SMV/Peg‐IFN/RBV combination therapy for genotype 1b HCV‐infected patients.