Wednesday, March 22, 2017

Hepatitis C Cures Lag While New Drugs Wait in the Wings

Hepatitis C Cures Lag While New Drugs Wait in the Wings
By Jessica Wapner On 3/22/17 at 12:28 PM

Four years ago, the first curative pills for hepatitis C virus (HCV) were handed to patients. These drugs were a breakthrough for people infected with this pathogen. Lacking in serious side effects and eradicating the virus from the body in just 12 weeks, these so-called direct-acting antivirals (DAAs) offered a clean escape from this potentially fatal liver illness.

But with numerous DAAs now available—along with their long trail of clinical trial data—primary care physicians are left to navigate a crowded and confusing landscape for treating HCV. Controversy surrounding the cost of these drugs has also become a concern.
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Harvoni Study: 97% of Hepatitis C Patients Cured

Of Interest
Mar 20, 2017
Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis.
Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child–Turcotte–Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without.

Prime Therapeutics Study Finds 97 Percent of Hepatitis C Patients Cured with Harvoni® Treatment
Mar 21, 2017

Real-world data show nearly all patients completing therapy were cured.

ST. PAUL, Minn. – Nearly all patients who completed at least eight weeks of hepatitis C treatment with Gilead’s Harvoni® (ledipasvir/sofosbuvir) were cured of the disease, according to Prime Therapeutics LLC (Prime). Prime, a pharmacy benefit manager (PBM) serving nearly 20 million members nationally will present the data next week at the Academy of Managed Care Pharmacy’s 2017 Annual Meeting. The results are similar to clinical trial data on the treatment, which found cure rates of 94 to 99 percent.

For the study, Prime researchers reviewed data from 311 individuals who received at least eight weeks of Harvoni therapy and had a sustained virologic response (SVR) test result provided to the pharmacy between 12 to 24 weeks following Harvoni use. The SVR is used determine treatment response. Researchers found 301 of 311 members (96.8 percent) had a SVR laboratory result indicating a cure.

“Prime’s real-world data reflect findings from clinical trials. Our members who received at least eight weeks of Harvoni through Prime Therapeutics Specialty PharmacyTM had a very high likelihood of being cured of this disease,” said Cathy Starner, PharmD, principal health outcomes researcher at Prime.
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Tuesday, March 21, 2017

“Waiting for DAAs”: A retrospective chart review of patients with untreated hepatitis C in Rwanda

“Waiting for DAAs”: A retrospective chart review of patients with untreated hepatitis C in Rwanda
Neil Gupta , Jules Kabahizi, Constance Mukabatsinda, Timothy David Walker, Emmanuel Musabeyezu, Athanase Kiromera, Jennifer Ilo Van Nuil, Kevin Steiner, Joia Mukherjee, Sabin Nsanzimana, Aimable Mbituyumuremyi

Full Text Article
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Published: March 21, 2017
http://dx.doi.org/10.1371/journal.pone.0174148

Abstract
Background
Access to treatment for hepatitis C virus (HCV) in sub-Saharan Africa is extremely limited. With the advent of direct acting antivirals (DAAs), highly effective and easy-to-deliver oral regimens are now available on the global market. This study was conducted to understand the background and characteristics of a national cohort of patients with HCV infection enrolled in care and awaiting therapy with DAAs.

Methods and findings
We conducted a retrospective chart review of all adult patients with confirmed HCV infection who were currently enrolled in care and treatment at the four existing hepatitis referral centers in Rwanda. Patient charts at these centers were reviewed, and routinely collected data were recorded and analyzed. Overall, 253 patients were identified; median age was 56 years (IQR: 43, 65), and 149 (58.9%) were female. Median viral load was 688,736 IU/ml and 96.7% were HCV genotype 4. As classified by FIB-4 score, 64.8% of the patients had moderate to severe fibrosis. Fibrosis stage was associated with age (OR 1.12, CI 1.09–1.17), but not with time since diagnosis, gender, treatment center, or type of insurance. There was a low frequency of documented co-morbid conditions, including hypertension, diabetes, HIV, and hepatitis B virus.

Conclusions
Compared to an estimated 55,000 patients eligible for HCV treatment in Rwanda, this study identified only 253 patients currently diagnosed and engaged in care, highlighting an immense treatment gap in HCV, likely due to the lack of accessible and affordable screening, diagnostic, and treatment modalities. The patients that were enrolled in care had a disproportionately advanced fibrosis stage, possibly indicating late presentation to care or lack of treatment options. In the context of newly available and effective treatment options, this study supports the overall need to accelerate access to HCV screening, diagnostics, and care and treatment services in resource-limited settings in sub-Saharan Africa.

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ZEPATIER® now covered in Quebec for the treatment of chronic hepatitis C 

ZEPATIER® now covered in Quebec for the treatment of chronic hepatitis C 

KIRKLAND, QC, March 21, 2017 /CNW Telbec/ - Merck Canada Inc. today announced that ZEPATIER® (elbasvir/grazoprevir) will be listed among the drugs covered by Quebec's health insurance board, the Régie de l'assurance maladie du Québec (RAMQ), as of March 22. Quebec joins other jurisdictions that have approved the product for reimbursement under their public healthcare plans for chronic hepatitis C patients presenting with recognized criteria. Zepatier is indicated for the treatment of chronic infection by genotypes 1, 3 or 4 of the hepatitis C virus in adults.

The product monograph, including detailed product information and indication, is available online by clicking here.

"This announcement reflects the hepatitis C agreement between Merck and the pan-Canadian Pharmaceutical Alliance (pCPA). We are proud to contribute a solution in the fight against this disease, all the while helping reduce the cost pressure on the healthcare system," says Chirfi Guindo, President and Managing Director of Merck Canada Inc.

Hepatitis C patients without significant hepatic fibrosis who present with certain comorbidities or specific conditions will be eligible for the treatment, including those who have chronic kidney disease, who are co-infected with the human immunodeficiency virus (HIV) or the hepatitis B virus (HBV), who have undergone an organ transplant or who present with extrahepatic manifestations of the disease.

"Zepatier, which was approved in Canada in 2016 for cirrhotic and non-cirrhotic patients with a genotype 1a, 1b or 4 infection who were not previously treated or who experienced relapse after previous treatment meets the unmet needs of some groups, including renally impaired and dialysis patients," adds Dr. Marc Poliquin, a gastroenterologist with the Clinique médicale du Quartier Latin. "It also makes it possible to continue simple anti-reflux treatments, especially for patients who cannot change their acid reflux therapy without interfering with the effectiveness of hepatitis C treatment."

If not treated in time, hepatitis C can lead to serious complications, such as cirrhosis, liver cancer or the need for a liver transplant.2 In 2013, costs related to HCV complications were estimated at $161.4 million in Canada (estimates range from $85.4 million to $251.5 million).

High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1.2 million men

Media Coverage On This Article
TUESDAY, March 21, 2017 (HealthDay News) -- Overweight and obese young men are at increased risk for serious liver disease or liver cancer later in life, and those with diabetes have an even higher risk, a new study warns.

Study

High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1.2 million men
Hannes Hagström1,2, Per Tynelius3,4, Finn Rasmussen5

Full Text Available Online

Significance of this study

What is already known on this subject?
  • Overweight and obesity is increasing in prevalence worldwide.
  • A high body mass index (BMI) is associated with an increased risk for future severe liver disease and hepatocellular carcinoma in adults.
  • A high BMI also increases the risk for type 2 diabetes mellitus (T2DM), which in turn is associated with an increased risk of severe liver disease.

What are the new findings?
  • High BMI in late adolescence is associated with future severe liver disease in a non-linear relationship.
  • This risk is even higher in men who also develops T2DM, but also relevant in men who do not develop T2DM.
  • High BMI in late adolescence is also associated with an increased risk of subsequent hepatocellular carcinoma.

How might it impact on clinical practice in the foreseeable future?
  • Men who are overweight in young adulthood should be informed about an increased risk of future severe liver disease, including hepatocellular carcinoma. This could affect future public health decisions.
  • Men who develop T2DM, independent of BMI early in young adulthood or midlife, is at increased risk of severe liver disease, should be informed of this risk and possibly screened for presence of manifest liver disease to prevent future mortality in liver disease.

Abstract
Objective A high body mass index (BMI) is associated with an increased risk for severe liver disease. It is unclear if this risk differs across BMI categories, and if the association is partially attributed to development of type 2 diabetes mellitus (T2DM).
Design We used register data from more than 1.2 million Swedish men enlisted for conscription between 1969 and 1996. Data regarding new events of severe liver disease and T2DM during follow-up were obtained by record-linkage of population-based registers. We used Cox regression to estimate adjusted HRs for future inpatient care and mortality in severe liver disease and incidence of hepatocellular carcinoma (HCC) across BMI categories, using BMI of 18.5–22.5 kg/m2 as reference.
Results During a follow-up of more than 34 million person-years, 5281 cases of severe liver disease including 251 cases of HCC were identified. An association with severe liver disease was found for overweight (HR 1.49, 95% CI 1.35 to 1.64) and for obese men (HR 2.17, 95% CI 1.82 to 2.59). Development of T2DM further increased the risk for severe liver disease across all BMI categories, for instance, men with obesity and T2DM had a higher risk of severe liver disease (HR 3.28, 95% CI 2.27 to 4.74) than men with obesity free of T2DM (HR 1.72, 95% CI 1.72 to 2.54).
Conclusions A high BMI in late adolescent men was associated with an increased risk of future severe liver disease, including HCC. Development of T2DM during follow-up was associated with a further increased risk of severe liver disease, independent of baseline BMI.

Full Text Article Available, here.

Monday, March 20, 2017

2017 / Hepatitis C: Down but Not Out - Oral Direct-Acting Agent Therapy for HCV

Media Coverage Of This Article
Will new hepatitis C treatments eliminate the virus for good?

NEJM Journal Watch
All FDA-Approved, Oral Direct-Acting Antivirals for Hepatitis C Safe and Effective for Genotype 1
By Kelly Young
Edited by Jaye Elizabeth Hefner, MD   
The FDA-approved interferon-free regimens for treating hepatitis C appear to be safe and effective, suggests an Annals of Internal Medicine review.

Researchers examined 42 randomized trials of oral hepatitis C treatments that included at least two direct-acting antivirals. Among the findings:
  • For genotype 1 infection, the most common HCV type, sustained virologic response rates were above 95% for six regimens.
  • For patients with HCV genotype 3 and without cirrhosis, sofosbuvir plus velpatasvir or daclatasvir for 12 weeks seemed to be most effective.
  • For genotype 3 with cirrhosis, velpatasvir-sofosbuvir had higher response rates. That drug combination was also highly effective (99% response rate) for genotypes 2, 4, 5, and 6.
  • Patient groups traditionally considered difficult to treat — including those with HIV, severe kidney disease, or liver transplant — had high response rates and limited adverse events.
Editorialists conclude that "hepatitis C is down but not out," noting that screening for HCV is not yet routine, and the drugs are still priced high.
NEJM Journal Watch

Editorials |21 March 2017
Annals of Internal Medicine
Hepatitis C: Down but Not Out
Jay H. Hoofnagle, MD; Averell H. Sherker, MD                   
Within the past 4 years, no fewer than 10 potent, orally available antiviral drugs have received U.S. Food and Drug Administration (FDA) approval as therapy for chronic hepatitis C virus (HCV) infection. These small molecules are directed at 1 of 3 HCV targets: NS3/4A protease (“-previrs” [simeprevir, paritaprevir, and grazoprevir]), NS5B RNA polymerase (“-buvirs” [sofosbuvir and dasabuvir]), or NS5A polypeptide (“-asvirs” [daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir]). Most important, combinations of 2 or 3 of these agents have proven highly effective in inducing a sustained virologic response (SVR), with persistent loss of HCV RNA from serum. Long-term follow-up of patients who have achieved SVR shows resolution of the accompanying liver disease and permanent loss of HCV RNA from both serum and the liver, suggesting a “cure” of the chronic viral infection. These new all-oral regimens typically have SVR rates of 95% or more with only 8 to 12 weeks of treatment and minimal adverse effects; in contrast, previous interferon-based regimens yielded rates of 50% to 60%, but only in highly selected patients and after 48 weeks of poorly tolerated treatment with serious adverse effects and significant contraindications. The new antiviral regimens have transformed management of chronic HCV infection.
http://annals.org/aim/article/2613307/hepatitis-c-down-out

Annals of Internal Medicine
Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review
Oluwaseun Falade-Nwulia, MBBS, MPH (*); Catalina Suarez-Cuervo, MD (*); David R. Nelson, MD; Michael W. Fried, MD; Jodi B. Segal, MD, MPH; Mark S. Sulkowski, MD
View Full Text Article Online

Abstract
Background:

Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection.Purpose:
To summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection.

Data Sources: MEDLINE and EMBASE from inception through 1 November 2016.Study Selection:

42 English-language studies from controlled and single-group registered clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs.

Data Extraction: Two investigators abstracted data on study design, patient characteristics, and virologic and safety outcomes sequentially and assessed quality independently.

Data Synthesis: Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child–Turcotte–Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without.

Limitations: Twenty-three studies had moderate risk of bias (10 were open-label single-group trials, 11 had limited information on concealment of the allocation scheme, and 5 had selective outcome reporting). All but 1 of the studies were industry-funded. Heterogeneity of interventions precluded pooling.

Conclusion:
Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis.

Primary Funding Source:Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42014009711)

In the United States, 3.2 to 5 million people are chronically infected with hepatitis C virus (HCV) and are at risk for cirrhosis, liver cancer, and death if untreated (1, 2). Infection with HCV is the primary indication for liver transplantation and causes more deaths than all other notifiable infectious diseases in the United States combined (3, 4). Cure of this infection, defined as the absence of detectable HCV RNA in the blood at least 12 weeks after treatment completion (sustained virologic response [SVR]), is strongly associated with reduced liver-related morbidity and mortality (5, 6). The development of drugs that directly inhibit key steps in viral replication has led to availability of several oral HCV treatment regimens (7). We systematically reviewed the efficacy and safety of oral interferon-free HCV treatment regimens that have been approved by the U.S. Food and Drug Administration (FDA) and include at least 2 direct-acting antivirals (DAAs). We also assessed the effect of ribavirin on rates of SVR and adverse events. We reviewed phase 2 and 3 clinical trial data for patients infected with HCV genotypes 1 to 6 and patients previously considered difficult to cure with decompensated cirrhosis, HIV infection, renal failure, or liver transplantation.

Methods
Data Sources and Searches
We developed a protocol for this systematic review and registered it in PROSPERO (CRD42014009711). We searched MEDLINE and EMBASE for literature published in English from inception through 1 November 2016. The search strategy included terms for HCV infection and the medications of interest (Figure 1). We also searched ClinicalTrials.gov and hand-searched the reference lists of included articles and related systematic reviews.

Study Selection

We included English-language, single-group, randomized, controlled trials (RCTs) of adults with chronic HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs. We included trials that used DAA combinations—including inhibitors of HCV NS3 protease (grazoprevir, paritaprevir, and simeprevir), NS5A (daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir), and NS5B polymerase (sofosbuvir and dasabuvir), as well as the oral antiviral ribavirin—and for which the primary outcome was SVR. We excluded studies published only as abstracts; dose-finding studies; those in which the primary outcome was pharmacokinetics; or those in which the regimens included interferon, DAAs that were not FDA-approved, or only 1 DAA (for example, sofosbuvir plus ribavirin). Trials were included regardless of participants' cirrhosis, HIV, or liver transplantation status, but trials of limited populations (for example, DAA-experienced patients or those of a single race) were excluded.

Data Extraction and Quality Assessment

Two reviewers independently screened titles and abstracts and then the full text of potentially eligible articles to identify studies meeting inclusion criteria. Using standardized forms, 1 reviewer extracted information from the selected studies about study characteristics, design, outcomes, and the funding source. A second reviewer confirmed the accuracy of the extractions. Differences were resolved through consensus. Two reviewers independently assessed risk of bias for each selected study by using 5 items from the Cochrane risk-of-bias tools for RCTs and a Cochrane tool for assessment of risk of bias in nonrandomized trials and observational studies (8, 9).

Data Synthesis and Analysis

Detailed evidence tables were generated, and studies were summarized by outcomes. The results were organized by genotype and then by the specific population studied. The heterogeneity of the interventions precluded quantitative pooling of results.

Role of the Funding Source

The Patient-Centered Outcomes Research Institute (PCORI) funded the study and reviewed the report but did not participate in the formulation of the review's questions, data searches, study appraisals, evidence interpretation, or the preparation or approval of the manuscript for publication.

Results
Study and Quality Characteristics

Of 1796 citations evaluated, we included 42 studies published in 40 articles (Figure 1). All but 1 of the studies were funded by industry (10). Ten were open-label, single-group studies (10–19); 5 had a placebo group with deferred treatment (20–24); 11 evaluated different durations of therapies and the addition of ribavirin (for example, 8 vs. 12 weeks or 12 vs. 24 weeks of therapy with or without ribavirin) (25–35); 5 evaluated the same duration of therapy with and without ribavirin (36–39); 6 evaluated different durations with ribavirin (40–45); and 3 evaluated different durations of therapy without ribavirin (46–48). Only 2 studies had an active comparator group receiving an HCV treatment regimen other than that being evaluated in the trial (49). Three studies had 48 weeks of posttreatment follow-up, whereas the remainder had 12 or 24 weeks of follow-up.

Of the 42 studies, 19 had low risk of bias and 23 had moderate risk. Sources of possible bias included single-group design (n = 10), lack of information on sequence generation or concealment of the allocation scheme (n = 11), and selective reporting of outcomes (n = 5). Because SVR is a highly objective outcome measure, lack of blinding was not considered an important threat to validity. Rates of loss to follow-up were low (<10% for all studies).

HCV Genotype 1 Infection

Thirty-two studies enrolled persons with HCV genotype 1 infection (Table; Figure 2, continued Figure 2; and Table 1 of the Supplement). Download Supplemental Content

Regimens That Include NS3/4A Protease Inhibitors

Grazoprevir–Elbasvir.

Grazoprevir is an NS3 protease inhibitor that is available in a fixed-dose combination with elbasvir, an NS5A inhibitor. This regimen was studied in 4 multicenter randomized trials published in 6 articles (11, 20, 21, 25–27). Risk of bias was moderate in 3 of these studies due to lack of a comparator group (n = 1) and selective reporting (n = 2). Daily grazoprevir–elbasvir for 12 weeks was associated with SVR rates of 92% and 99% to 100% in treatment-naive and treatment-experienced patients with genotype 1a and 1b infection, respectively (20, 26, 27). Among patients with genotype 1a but not genotype 1b infection, lower SVR rates were associated with pretreatment presence of naturally occurring resistance-associated substitutions (RASs) at positions 28, 30, 31, and 93 of the NS5A region (20, 27). Prolongation of therapy to 16 weeks and addition of ribavirin led to SVR among 49 treatment-experienced patients, including all 6 patients with baseline NS5A RASs (27). Ribavirin was associated with greater incidence of anemia (3% to 16% vs. 0%), fatigue, and nausea (25–27). With the exception of patients with genotype 1a infection with baseline RASs, the SVR rate was similar in those treated with or without ribavirin. Cirrhosis was not associated with lower SVR rates (14, 16).

Paritaprevir–Ritonavir–Ombitasvir and Dasabuvir.

Paritaprevir is an NS3 protease inhibitor that is coformulated with ritonavir (to provide pharmacologic boosting) and ombitasvir (an NS5A inhibitor). For patients with genotype 1 infection, dasabuvir (a nonnucleoside NS5B polymerase inhibitor) was added. We identified 1 study with low risk of bias that used the two-DAA regimen without dasabuvir (45) and 9 studies (5 with low risk of bias and 4 with moderate risk of bias) that used the three-DAA regimen for 12 or 24 weeks (12, 13, 22, 23, 37, 38, 40, 41). Moderate risk of bias was due to lack of a comparator group (n = 2) and unclear sequence generation and allocation scheme concealment (n = 2). The three-DAA regimen without ribavirin yielded lower SVR rates in persons with genotype 1a infection (90%) than those with genotype 1b infection (99%); however, with the addition of ribavirin, the SVR rate among noncirrhotic patients with genotype 1a infection increased to 97% (38). Compared with placebo, ribavirin was associated with more anemia, fatigue, insomnia, and rash (22, 38). Among cirrhotic patients with genotype 1a infection, the three-DAA regimen plus ribavirin for 24 weeks led to higher SVR rates than 12 weeks of treatment (94.2% vs. 88.6%) (41). High rates of SVR were seen among cirrhotic and noncirrhotic patients with genotype 1b infection treated for 12 weeks with the three-DAA regimen alone or with ribavirin (97% to 100%) (22, 23, 37, 38, 41, 45).

Simeprevir and Sofosbuvir.

Simeprevir is an NS3 protease inhibitor that is used once daily in combination with sofosbuvir, a nucleoside analogue NS5B polymerase inhibitor. We identified 3 studies using this regimen (14, 28, 46). Risk of bias was moderate in 2 studies due to unclear sequence generation (n = 1) and lack of a comparator group (n = 1). When used for 12 weeks, the regimen was associated with high rates of SVR (97%) in persons with HCV genotype 1a or 1b infection without cirrhosis (46). In this population, pretreatment presence of naturally occurring simeprevir RASs at position 80 of the NS3 region (Q80K) was not associated with lower SVR rates (46). However, lower SVR rates were observed among patients with cirrhosis (79% to 88%) and, in this population, the presence of the Q80K RAS was associated with lower SVR rates in patients with genotype 1a infection (74% with Q80K and 92% without) (14).

Regimens That Do Not Include NS3/4A Protease Inhibitors

Daclatasvir and Sofosbuvir.

Daclatasvir is an NS5A inhibitor used with sofosbuvir. Clinical trial data on this combination are limited but suggest high SVR rates with 12- and 24-week treatment (96% to 100%), based on data from 2 studies with moderate risk of bias (29, 48). Among patients with advanced liver disease, SVR rates were lower (82%) (15).

Ledipasvir–Sofosbuvir.

Ledipasvir, an NS5A inhibitor, is coformulated with sofosbuvir as a once-daily tablet. Eight studies (4 with low risk of bias and 4 with moderate risk of bias) evaluated different treatment durations (8, 12, and 24 weeks) and the addition of ribavirin (17, 30–34, 43, 44). Moderate risk of bias was due to lack of a comparator (n = 1) and unclear sequence generation or allocation scheme concealment (n = 3). In treatment-naive patients, SVR rates were greater than 95% with 12 weeks of treatment, and longer treatment did not yield higher rates (30, 31, 33). Although 8 weeks of therapy was assessed in 1 RCT and was found to lead to high SVR rates in noncirrhotic persons with pretreatment HCV RNA levels less than 6 × 106 IU/mL (33), the most data on efficacy are for 12 weeks. In treatment-naive patients, ribavirin was not associated with higher SVR rates regardless of cirrhosis status, whereas in treatment-experienced patients, either longer therapy (24 weeks) with ledipasvir–sofosbuvir or the addition of ribavirin to the regimen for 12 weeks was associated with higher SVR rates in patients with cirrhosis (97% vs. 96%) (34). The addition of ribavirin led to more adverse events, notably anemia, fatigue, and insomnia (31–33).

Velpatasvir–Sofosbuvir.

Velpatasvir, a pangenotypic NS5A inhibitor, is coformulated with sofosbuvir as a once-daily tablet. This regimen for 12 weeks was associated with high SVR rates (97% to 99%) in patients with HCV genotype 1a or 1b infection, including those with cirrhosis and prior treatment experience (24). In this placebo-controlled, double-blind trial with low risk of bias, the incidence of adverse events was similar in patients receiving velpatasvir–sofosbuvir and those receiving placebo.

HCV Genotype 2 Infection

Six studies enrolled patients with HCV genotype 2 infection (Table and Figure 3); 3 studies (2 with low risk of bias and 1 with moderate risk of bias) evaluated the fixed-dose combination of velpatasvir–sofosbuvir (24, 35, 49), and 3 with moderate risk of bias evaluated daclatasvir plus sofosbuvir (15, 29, 48).

Daclatasvir and Sofosbuvir

In the ALLY-2 study, all 13 HIV-infected patients with genotype 2 infection who were treated for 12 weeks achieved SVR (48). In another study, 24 of 26 (92%) treatment-naive, noncirrhotic, HIV-seronegative patients treated for 24 weeks with or without ribavirin achieved SVR; 2 patients were lost to follow-up (29).

Velpatasvir–Sofosbuvir

The ASTRAL-1 and ASTRAL-2 studies reported SVR in 237 of 238 patients (99%) with genotype 2 infection who received velpatasvir–sofosbuvir for 12 weeks; 1 patient was lost to follow-up (24, 49). Rates of SVR were not affected by cirrhosis or prior treatment experience. In an RCT, velpatasvir–sofosbuvir was superior to sofosbuvir plus ribavirin (SVR of 99% vs. 94%) and was associated with fewer adverse events (49).

HCV Genotype 3 Infection

Eight studies enrolled patients with HCV genotype 3 infection (Table and Figure 3).

Daclatasvir and Sofosbuvir

In a phase 2 study, 16 of 18 noncirrhotic patients treated with or without ribavirin for 24 weeks achieved SVR (29). In the single-group ALLY-3 trial, which had moderate risk of bias, 94% to 97% of noncirrhotic treatment-naive and treatment-experienced patients achieved SVR with 12 weeks of treatment (16). In the same study, cirrhosis was associated with a marked reduction in SVR (58% to 69%) (16). The addition of ribavirin to the regimen for 12 or 16 weeks in patients with advanced liver disease led to SVR in 86% of cirrhotic patients (n = 36) in the ALLY-3+ study, which had moderate risk of bias due to unclear sequence generation and allocation scheme (42).

Ledipasvir–Sofosbuvir

In a single-center study with low risk of bias, all 26 treatment-naive patients treated with ledipasvir–sofosbuvir plus ribavirin for 12 weeks achieved SVR (39). The SVR rate was lower without ribavirin (64%) and in treatment-experienced patients (82%) (39).

Velpatasvir–Sofosbuvir

In a phase 3 RCT with 552 patients and low risk of bias, velpatasvir–sofosbuvir for 12 weeks (95%) was superior to sofosbuvir plus ribavirin for 24 weeks (80%) and was associated with fewer adverse events, particularly less anemia (49). Lower SVR rates were observed in patients with pretreatment presence of velpatasvir NS5A RASs, particularly at position 93 (88%), compared with those without RASs (97%).

HCV Genotype 4 Infection

Twelve studies enrolled persons with HCV genotype 4 infection (Table and Figure 3).

Grazoprevir–Elbasvir

In the C-EDGE study, efficacy of grazoprevir–elbasvir was demonstrated among 18 of 18 treatment-naive patients with genotype 4 infection (SVR of 100%) who received the regimen for 12 weeks; baseline presence of NS5A RASs did not affect SVR (20). Among treatment-experienced patients in a randomized trial of 12 or 16 weeks of the regimen with or without ribavirin, SVR rates were below 95% in all groups except patients who received 16 weeks of the regimen with ribavirin (27).

Paritaprevir–Ritonavir–Ombitasvir

In 1 trial with low risk of bias, paritaprevir–ritonavir–ombitasvir plus ribavirin resulted in high efficacy (SVR of 100%) in both treatment-naive (n = 42) and treatment-experienced (n = 44) patients with genotype 4 infection (36). The absence of ribavirin was associated with a lower SVR rate (91%).

Simeprevir and Sofosbuvir

In an RCT with moderate risk of bias due to unclear sequence generation and allocation scheme concealment, simeprevir plus sofosbuvir was associated with SVR in all 43 patients (100%) treated for 12 weeks, including those with cirrhosis (n = 23); however, SVR rates were lower in 20 patients treated for 8 weeks (75%) (47).

Ledipasvir–Sofosbuvir

In a single-group trial of 21 patients, 95% who received 12 weeks of ledipasvir–sofosbuvir achieved SVR; the study included few patients with cirrhosis (n = 7) or prior treatment experience (n = 8) (10). In a similar trial conducted in France, 41 of 44 patients (93%) who were treated for 12 weeks achieved SVR (19). No serious adverse events were reported in these studies (10, 19).

Velpatasvir–Sofosbuvir

In the ASTRAL-1 RCT, which had low risk of bias, velpatasvir–sofosbuvir led to SVR in all 116 treatment-naive and treatment-experienced patients (100%) who were treated, including those with cirrhosis (24).

HCV Genotype 5 and 6 Infection

Six studies enrolled persons with HCV genotype 5 and/or 6 infection (18, 20, 24, 27, 35, 39) (Figure 3).

Ledipasvir–Sofosbuvir

This combination led to high SVR rates in persons with genotype 5 (n = 41; SVR of 95%) and genotype 6 (n = 25; SVR of 96%) infection (18, 39). Although the numbers of patients in these subgroups were small, SVR rates were high in treatment-experienced patients (≥95%) and those with cirrhosis (89%) (18).

Velpatasvir–Sofosbuvir

In 1 RCT with low risk of bias, patients with genotype 5 (n = 35) and genotype 6 (n = 41) infection achieved high rates of SVR (97% and 100%, respectively) with 12 weeks of treatment; only 1 patient did not achieve SVR (death unrelated to treatment) (24).

Subpopulations

Patients With HIV Co-infection

Direct-acting antiviral regimens used for 12 or 24 weeks showed high SVR rates (91% to 98%) and low adverse event rates (<10%). These rates were similar to those observed in persons without HIV (11, 17, 26, 40, 48). Shorter therapy (8 weeks) was evaluated in 1 RCT of daclatasvir plus sofosbuvir and led to lower rates of SVR (76%) than 12 weeks of therapy (97%) (48).

Patients With Decompensated Cirrhosis

Relatively few patients with decompensated liver disease (for example, those with jaundice, ascites, encephalopathy, or variceal hemorrhage) have been enrolled in DAA trials. Because of impaired metabolism, NS3 protease inhibitors are not recommended (simeprevir) or are contraindicated (paritaprevir or grazoprevir) in patients with Child–Turcotte–Pugh class B and C disease. These patients have been treated in trials of sofosbuvir plus NS5A inhibitors, including daclatasvir, ledipasvir, and velpatasvir (15, 35, 43, 44). In 1 RCT, velpatasvir–sofosbuvir with ribavirin for 12 weeks was more effective than velpatasvir–sofosbuvir alone for 12 or 24 weeks; however, ribavirin was associated with more treatment discontinuation due to adverse events (35). Across all studies, rates of serious adverse events were higher in patients with decompensated cirrhosis (10% to 52%) than in the general HCV patient populations (<10%).

Patients After Liver Transplantation

Four trials evaluated DAAs in patients who had undergone liver transplantation. Overall, SVR rates observed in these trials were similar to those reported in patients without a transplant (12, 15, 43, 44). However, among liver transplant patients with decompensated liver disease due to recurrent HCV infection, SVR rates were lower (50% to 80%) and adverse event rates were higher (16% to 75%) than those observed in liver transplant patients with compensated cirrhosis or those with minimal liver disease (6% to 21%) (12, 43, 44).

Patients With Chronic Kidney Disease

In 2 studies of patients with advanced renal dysfunction, including those receiving hemodialysis, high SVR rates were reported in those with HCV genotype 1 infection (13, 21). In 1 study with low risk of bias, grazoprevir–elbasvir for 12 weeks resulted in SVR in 94% of patients (n = 111) (21). In a smaller study with moderate risk of bias due to lack of a comparator group, a regimen of paritaprevir–ritonavir–ombitasvir and dasabuvir was effective (SVR of 90%), but ribavirin, which was used for patients with genotype 1a infection, was poorly tolerated and was discontinued due to adverse events in 8 of 14 patients (48).

Discussion
Multiple interferon-free, oral DAA regimens are available for treatment of chronic HCV infection. We found high SVR rates for all FDA-approved DAA regimens, with some evidence of variable response influenced by specific patient and virus characteristics. Rates of serious adverse events (<10%), loss to follow-up (<10%), and treatment discontinuation (<5%) were low even in patients with comorbid conditions, such as HIV infection and cirrhosis.

The evidence was robust for persons with genotype 1 infection, which is the most common genotype worldwide, infecting approximately 84 million persons (50). We reviewed 6 distinct DAA regimens for genotype 1 infection, with SVR rates greater than 95% for most drug combinations and patient populations. Our findings represent an important update of other systematic reviews of DAA regimens with and without interferon for treatment of HCV genotype 1 infection, which reported SVR rates in the range of 95% (50, 51) and 92% (52). The high treatment response rates in persons with genotype 1 infection are particularly important in light of the historically poor SVR rates observed with interferon in this population.

In contrast, fewer DAA regimens are available and effective for the treatment of HCV genotype 3 infection, which is the second most prevalent HCV genotype globally, infecting approximately 54 million persons. Our findings indicate that the most effective DAA regimens for patients who have genotype 3 infection without cirrhosis are sofosbuvir plus the NS5A inhibitors velpatasvir or daclatasvir for 12 weeks, whereas higher SVR rates were observed with velpatasvir–sofosbuvir in patients with cirrhosis. This agrees with recent systematic reviews, identified through MEDLINE searches from 2014 to 2016, that identified velpatasvir–sofosbuvir as the most effective treatment for genotype 3 infection (51, 52). Our findings also suggest that lower SVR rates were achieved in patients with compensated and decompensated cirrhosis, prior treatment experience, or NS5A RASs; the addition of ribavirin and longer treatment duration were associated with higher SVR rates in these patient groups (42, 53).

Although relatively few studies enrolled patients with genotype 2, 4, 5, or 6 infection, high rates of SVR (>92%) were observed for all regimens administered for at least 12 weeks. Rates of SVR were particularly high (99%) for patients with genotype 2, 4, 5, or 6 infection treated with velpatasvir–sofosbuvir (24). For treatment of genotype 4 infection, all but 1 of the DAA regimens (paritaprevir–ritonavir–ombitasvir) led to high SVR rates (93% to 100%) without ribavirin and were associated with minimal adverse effects in treatment-naive patients.

Oral DAA regimens also showed high SVR rates and minimal adverse events in patient populations that were poorly responsive or could not be treated with interferon, including those with HIV co-infection, decompensated cirrhosis, severe chronic kidney disease, and a liver transplant. Patients co-infected with HIV and HCV and those receiving immunosuppressive agents after liver transplantation had SVR rates similar to those of persons without immune dysfunction, suggesting that oral DAAs mitigate the effect of an impaired HCV immune response (54–56). Direct-acting antiviral options for persons with severe chronic kidney disease remain limited, and although high SVR rates (85% to 100%) were observed in 2 RCTs for persons with HCV genotype 1 infection, no trials were identified in persons with genotype 2 or 3 infection, for whom interferon is still recommended (57). Treatment options also remain limited in patients with decompensated liver disease. Current NS3 protease inhibitors are hepatically metabolized and are contraindicated in this population; as such, trials have been restricted to sofosbuvir plus NS5A inhibitors. The evidence indicates that these regimens provide high rates of SVR (>85%), but serious adverse events are common (10% to 52%). In addition, questions remain with regard to the long-term clinical benefit of cure of HCV infection in persons with severe liver dysfunction.

Across multiple trials, our findings indicate that ribavirin continues to have a role in maximizing SVR rates in certain patients, including those with genotype 1a or 3 infection, cirrhosis, or prior treatment experience. Clinical trials for patients with decompensated cirrhosis and a liver transplant have also largely included ribavirin. Although ribavirin was associated with an increase in anemia, fatigue, and insomnia, the rates of serious adverse events and treatment discontinuation were similar in patients treated with and without it.

Limitations of this study include the fact that safety data from clinical trials may not fully represent patient experience in clinical practice. Persons with chronic hepatitis B virus infection were excluded from trials, and the risk for hepatitis B virus reactivation was not examined. We also included noncontrolled trials; however, spontaneous cure of HCV infection is rare. Most of the studies were industry-funded; such studies are more likely to be published if results are favorable (58), but we are not aware of large, unpublished studies in this field and the risk of bias with the objective outcome of SVR is low. The heterogeneity of the interventions studied also prevented quantitative pooling of results, and the relatively short follow-up limits our ability to comment on late relapse of HCV infection. Several studies were also population-specific, thus limiting generalizability of findings to all patients. Given the multitude of effective oral DAA regimens with similar rates of SVR and adverse events, RCTs will be needed to determine the best HCV treatments for different patient populations. One such trial, the PRIORITIZE study (ClinicalTrials.gov: NCT02786537), is under way in persons with genotype 1 infection (59).

Finally, our systematic review is limited by the rapidly evolving HCV treatment landscape and the inability to include all DAA regimens in ongoing or recently completed clinical trials that we identified on ClinicalTrials.gov (Table 7 of the Supplement). These ongoing clinical trials include 2 novel nucleotide analogue NS5B polymerase inhibitors, MK-3682 and AL-335, which are being evaluated in combination with approved NS3 protease inhibitors and novel NS5A inhibitors (ruzasvir and odalasvir), as well as 2 novel pangenotypic NS3 protease inhibitors, voxilaprevir and glecaprevir, which are being evaluated in combination with approved (sofosbuvir–velpatasvir–voxilaprevir) and novel (glecaprevir–pibrentasvir) DAAs (60).

In conclusion, oral DAA regimens that are highly efficacious, well-tolerated, and relatively short in duration are now available for all HCV genotypes and for patient populations historically considered difficult to cure. The ease of dosing, safety profile, and effectiveness of these agents provide an opportunity to expand the number of patients who can be treated for HCV infection and the pool of treating providers. Rapid developments in oral DAA therapies can be beneficial only if they are linked to efforts to improve rates of HCV detection, linkage to care, and access to DAA therapy.

References
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Quebec Broadens Access - Listing of EPCLUSA™ tablets effective on March 22 , 2017

EPCLUSA™, to treat all six genotypes of chronic hepatitis C infection, added to the Liste des médicaments de la RAMQ

-- Quebec Broadens Access for Patients with Less Advanced Disease Who Have Other Health Conditions --

MISSISSAUGA, ON , March 20, 2017 /CNW/ - Gilead Sciences Canada, Inc. ( Gilead Canada ) commends the continued leadership of Quebec in the treatment of hepatitis C with the listing of EPCLUSA™ (sofosbuvir/velpatasvir) tablets effective on March 22 , 2017. 

EPCLUSA is the first once-daily, pan-genotypic single tablet regimen for the treatment of adults with genotype 1-6 chronic hepatitis C virus (HCV) infection. 

This listing will support patients to access curative therapy in Quebec , and is a significant contribution to advancing Canada's efforts to achieving its World Health Organization commitment to eliminate hepatitis C by 2030.

EPCLUSA, one tablet taken daily for 12 weeks, is for use in adult patients without cirrhosis or with compensated cirrhosis, and in combination with ribavirin (RBV) for those with decompensated cirrhosis.  It is also the first single tablet regimen approved for the treatment of patients with genotypes 2 and 3, without the need for RBV. 

The approval of EPCLUSA was supported by data from four international Phase 3 studies, ASTRAL-1, ASTRAL-2, ASTRAL-3 and ASTRAL-4.  Of the 1,035 patients without cirrhosis or with compensated cirrhosis treated with EPCLUSA for 12 weeks in the ASTRAL-1, ASTRAL-2 and ASTRAL-3 studies, 1,015 (98 per cent) achieved SVR12 (sustained virologic response 12 weeks after the end of treatment).  In ASTRAL-4, patients with decompensated cirrhosis who received EPCLUSA with RBV for 12 weeks achieved a high SVR12 rate (94 per cent) compared to those who received EPCLUSA for 12 weeks or 24 weeks without RBV (83 per cent and 86 per cent, respectively).  The most common adverse events in the four ASTRAL studies were headache and fatigue, and were comparable in incidence to the placebo group included in ASTRAL-1.

New médicament d'exception criteria for SOVALDI® (sofosbuvir), HARVONI® (ledipasvir/sofosbuvir) and EPCLUSA will increase access to patients with a lower stage of disease and poor prognosis.  These new criteria are available on the RAMQ website.


"We now have the ability to cure almost all patients with chronic HCV with a simple, safe and effective 12-week treatment, regardless of genotype or patient history," said Dr. Peter Ghali , Hepatologist, and Program Director, Hepatology training, McGill University Health Centre.  "Broader access to EPCLUSA, particularly at the earlier stage of the disease, means that we can move more quickly to help patients achieve a cure and improve their quality of life, while saving valuable funds associated with the significant long-term burden of illness and costs to the healthcare system."

The Institut national de la santé publique du Québec (INSPQ) estimates that between 40,000 to 75,000 people in the province could have chronic hepatitis C infection.  Between 1990 and 2014, 39,700 individuals were identified with hepatitis C.  In 2015, an additional 1,073 cases were identified, thus supporting the importance of access to treatment to prevent the future complications of the disease.1   There are six genotypes of hepatitis C.  Genotype 1 infection is the most prevalent genotype representing 62 per cent of infected individuals.  Genotypes 2 and 3 account for approximately 6.9 per cent and 25 per cent of infections, whereas genotypes 4, 5, and 6 are less prevalent in Québec at 6.1 per cent.2

"We are very pleased that access to treatments is now expanded to a broader population of hepatitis C patients in our province," said Laurence Mersilian, Executive Director, The Centre and Association for People Living with Hepatitis C (CAPAHC).  "We wish to thank and congratulate the Government of Quebec for its continued leadership and commitment to care for those living with hepatitis C."

" Gilead Canada is pleased that INESSS (Institut national d'excellence en santé et services sociaux) and the Ministry of Health and Social Services are recognizing the innovation and clinical value of EPCLUSA for the treatment of all genotypes of hepatitis C in a single tablet regimen," said Kennet Brysting, General Manager, Gilead Canada .  "Broader treatment access for patients will potentially have a profound impact on disease elimination efforts in Canada , and supporting such efforts is a key priority for our company.  We will continue to work closely with all jurisdictions to bring this simple and cost-effective curative treatment to all eligible patients, regardless of their genotype or stage of fibrosis."
http://finance.yahoo.com/news/epclusa-treat-six-genotypes-chronic-162500978.html

Elimination of Hepatitis B: Is It a Mission Possible?

Elimination of Hepatitis B: Is It a Mission Possible?
Tai-Chung Tseng and Jia-Horng Kao
BMC Medicine201715:53 DOI: 10.1186/s12916-017-0820-x©
2017 Received: 9 December 2016
Accepted: 16 February 2017
Published: 15 March 2017

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Abstract
Chronic hepatitis B virus (HBV) infection is a global public health issue. Although the disease cannot be cured effectively, disease management has been improved over the past decade. The introduction of potent nucleos(t)ide analogues (NAs) to suppress viral replication represented a giant leap in the control of this disease. It has been shown that tenofovir treatment, a potent NA, complements current immunoprophylaxis to diminish mother-to-infant transmission in pregnant women with a high viral load. For patients with chronic HBV infection, quantitative hepatitis B surface antigen is a useful tool to define inactive carriers and to guide antiviral therapy. Quantification of HBV mutants is also useful in predicting long-term outcomes more precisely than ever. The next challenge is how to achieve an HBV cure; although immunotherapy is a promising strategy, the current results from two clinical trials using therapeutic vaccines to induce HBV-specific immune response in patients with chronic HBV infection are disappointing. In the coming years, we are expecting to see a combination of therapeutic agents with various modes of action to complete the mission of HBV elimination.

HCV over 3 decades: From a disease with no name to a cure

HCV over 3 decades: From a disease with no name to a cure
Infectious Disease News, March 2017
To mark our 30th anniversary, Infectious Disease News will be examining some of the infectious diseases that have defined and changed the field over the past 3 decades

At the American Association for the Study of Liver Diseases annual meeting in 2011, Ed Gane, MBChB, MD, FRACP, MNZM, presented data on PS7977, an antiviral agent for the treatment of hepatitis C virus infection. The treatment approach changed slightly across patient groups — some participants were treated for longer than others, and some received PS7977 in combination with ribavirin and pegylated interferon — but the results were always the same.
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Of Interest
Hepatitis C Timeline
This timeline spans from the first recorded references to hepatitis epidemics, to the 1989 discovery of the hepatitis C virus, ending with the FDA approved treatments used today.