Making Hepatitis C A Rare Disease In The United States

Making Hepatitis C A Rare Disease In The United States
Victor Roy, Dave Chokshi, Stephen Kissler, and Prabhjot Singh

New breakthrough medicines for Hepatitis C present an important choice about setting goals and taking systemic action to achieve public health advances in the United States. Despite appearing to offer cure rates greater than 90 percent, high-priced Hepatitis C drugs have driven treatment rationing since their approval over two years ago. Gaps in the screening, diagnosis, and treatment of Hepatitis C pose significant public health consequences.

Target: A ‘Rare Disease’ By 2025

Multiple indicators could be used to define such a target for Hepatitis C, such as deaths averted, percent treated and/or cured, incidence, or population prevalence. We demonstrate one possible approach, using a model published last November in Health Affairs by Van Nuys and colleagues. With a baseline scenario of using older interferon-based therapies, the model considered three treatment scenarios for Hepatitis C with the newest medicines: treat patients with advanced disease, treat all diagnosed patients regardless of disease stage, or treat 5 percent of diagnosed patients across all disease stages. They found that the option of treating 5 percent of the infected population annually would best balance potential benefits with affordability.

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Hepatitis C and beyond: Never a dull moment

Published on Jun 13, 2016

Hepatitis C and beyond: Never a dull moment

Air date: Wednesday, June 8, 2016, 3:00:00 PM

Category: WALS - Wednesday Afternoon Lectures

Runtime: 01:03:03

Description: NIH Director’s Wednesday Afternoon Lecture Series

The Annual George Khoury Lecture

From the emergence of a mystery virus associated with post-transfusion hepatitis to the discovery of the hepatitis C virus (HCV), we are now witnessing a remarkable new era of highly effective, curative treatments. Despite this, challenges remain to effectively implement these medical advances on a national and global scale. For the molecular virologist, many questions remain unanswered. Why are clinical isolates of HCV so difficult to culture? What is the link between chronic HCV and liver cancer? Where did HCV come from and should we rest on our laurels assuming that hepacivirus-associated disease will soon vanish? These and other topics will be the subject of this Khoury lecture.

For more information go to https://oir.nih.gov/wals

Author: Charles M. Rice, Ph.D., The Rockefeller University

Permanent link: http://videocast.nih.gov/launch.asp?1...

New Combination Therapy May Be Effective Against Chronic HCV Infection

New Combination Therapy May Be Effective Against Chronic HCV Infection
By Will Boggs MD
June 14, 2016

NEW YORK (Reuters Health) - The new NS3/4A protease inhibitor GS-9857, in combination with sofosbuvir and velpatasvir (SOF/VEL), produces sustained viral response in most patients with hepatitis C virus (HCV) genotype 1 or 3 infections, according to a phase 2 trial from Gilead Sciences.

Various combinations of direct-acting antiviral agents (DAAs) provide sustained virologic responses in most patients infected with HCV, but there are ongoing efforts to optimize and shorten regimens.

Dr. Edward J. Gane from Auckland City Hospital in New Zealand and colleagues evaluated the efficacy and safety of short-duration regimens (four, six, or eight weeks) of SOF/VEL plus GS-9857 in a broad range of patients with genotype 1 (n=120) and 3 (n=41) HCV infections, including 63 treatment-naïve patients and 98 previously-treated patients.

Sustained viral response at 12 weeks (SVR12) was achieved by 27% of treatment-naïve patients with genotype 1 infection without cirrhosis after four weeks of treatment and by 93% after six, the team reports in Gastroenterology, online May 27.

SVR12 was 87% among treatment-naïve patients with cirrhosis after six weeks of treatment, while it was 67% among DAA-experienced patients with and without cirrhosis. In patients who had received other previous treatment and did or did not have cirrhosis, SVR12 with eight weeks of therapy ranged from 89% to 100%.

Among patients with genotype 3 infection, SVR12 was achieved by 83% of treatment-naïve patients with cirrhosis after six weeks of treatment and by 100% of previously treated patients with or without cirrhosis after eight weeks of treatment.

Of the 30 patients who did not achieve SVR12, 28 had virologic relapse after completing treatment, one withdrew consent four weeks after the treatment ended (at which time the patient had undetectable HCV RNA), and one never attained HCV RNA below 15 IU/mL on treatment.

Relapse rates were 73% among patients who received only four weeks of treatment, 19% among those who received six weeks of treatment, and 4% among those who received eight weeks of treatment.

SVR12 rates were also high among patients who had resistance-associated substitutions at baseline (84%-86%, depending on the threshold), and no treatment-emergent resistance-associated substitutions were detected in 26 of 28 patients who relapsed.

Common adverse events included headache, nausea, fatigue, and diarrhea, most of which were mild in severity. No patient discontinued treatment due to an adverse event.

"These results suggest that 8 weeks is the threshold of treatment duration with combination DAAs for the easier-to-treat patient population, not 4 or 6 weeks as suggested by recent viral kinetic models," the researchers note. "Future attempts to shorten duration of DAA regimens to less than 8 weeks will probably require the addition of a host-targeting agent such as RG-101, an miR-122 antagonist, which has been shown to do so in the interim results of an ongoing phase 2 study."

"SOF/VEL/GS-9857 is now coformulated as a single tablet which is being evaluated in the larger Phase III program, which includes different patient populations, including DAA-experienced patients," they add. "This group of DAA-experienced patients is growing and currently represents an unmet medical need."

Dr. Assy Nimer from Ziv Medical Center in Haifa, Israel, who has studied various aspects of HCV infection and its treatment, told Reuters Health by email, "The most interesting or surprising results is the low rate of SVR at week 4 in naïve HCV genotype 1 patients without cirrhosis, indicating that the combination of three potent DAA is not effective for 4 weeks but is highly effective for 8 weeks of treatment."

"The best treatment duration of the new DAA combination would be between 8 and 12 weeks," he concluded, adding that "this type of new medications will likely be effective in minimizing resistance-associated variants (RAV), which persist for years."

Gilead Sciences supported the trial, employed several authors, and had various relationships with the rest, including Dr. Gane.

Dr. Gane did not respond to a request for comments.

http://www.journalofclinicalpathways.com/news/new-combination-therapy-may-be-effective-against-chronic-hcv-infection

SOURCE: http://bit.ly/1UaduVG

Gastroenterology 2016.

Hep C sufferers angered by activist website ban - fixhepc website will be geoblocked

A website which raises awareness about a medical cure for hepatitis C could be hidden from Australians.
11:09pm, Jun 14, 2016
Richard Woolveridge

Hepatitis C patients are angry and perplexed that the government’s drug regulator is backing a campaigning website into a corner where it feels it has no choice but to make the site invisible to Australians.

The fixhepc website has been making thousands of sufferers aware of an affordable cure for their lethal illness since it launched last October seeing an initial audience of 5000 visitors mushroom to six million visits over seven months.

But from Wednesday, the fixhepc website will be geoblocked, meaning people using computers with Australian IP addresses will not be able to see it or the information it contains about a disease which affects nearly a quarter of a million Australians. Any of the 150 million sufferers elsewhere in the world will still be able to see the site.

Why?
The Therapeutic Goods Administration has threatened the website’s campaigning founder Dr James Freeman, of Tasmania, with legal action because it argues his site “appears to promote the use and supply of prescription-only medicines”, an offence under Australian law.

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Comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin vs. ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin HCV genotype 1 patients

Original Article

Comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin vs. ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin in 6961 genotype 1 patients treated in routine medical practice

Authors •L. I. Backus,
author notes Corresponding author1.Department of Veterans Affairs, Population Health Services, Palo Alto Health Care System, Palo Alto, CA, USA
First published: 13 June 2016
Full publication history •DOI: 10.1111/apt.13696

View Full Text Article

Summary
Background Real-world data are needed to inform hepatitis C virus (HCV) treatment decisions.

Aim

To assess the comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin (LDV/SOF ± RBV) vs. ombitasvir/paritaprevir/ritonavir + dasabuvir (OPrD) ± RBV in genotype 1 HCV patients treated in routine medical practice.

Methods

Observational intent-to-treat cohort of genotype 1 patients initiating 8 or 12 weeks of LDV/SOF ± RBV or 12 weeks of OPrD ± RBV. Sustained virological response (SVR) required RNA below the limit of quantification at least 10 weeks after end of treatment.
Results 6961 patients initiated LDV/SOF (N = 4478), LDV/SOF + RBV (N = 1269), OPrD (N = 297), and OPrD + RBV (N = 917) at 126 facilities. Intention-to-treat SVR rates were 91.4% (3813/4170) for LDV/SOF, 90.0% (1098/1220) for LDV/SOF + RBV, 95.1% (269/283) for OPrD and 85.8% (746/869) for OPrD + RBV. SVR rates in those completing 8 weeks of LDV/SOF were 91.7% (1223/1333) and 12 weeks of LDV/SOF 94.6% (2475/2615), LDV/SOF + RBV 92.2% (1033/1120), OPrD 98.0% (248/253) and OPrD + RBV 95.5% (705/738). Significant predictors of SVR were African American race (OR 0.71, 95%CI 0.59–0.86, P < 0.001), body mass index (BMI) > 30 kg/m2 (OR 0.73, 95% CI 0.60–0.89, P = 0.002), FIB4 > 3.25 (OR 0.60, 95% CI 0.49–0.72, P < 0.001), OPrD + RBV compared to LDV/SOF (OR 0.60, 95% CI 0.48–0.76, P < 0.001) and subtype 1b (OR 1.38, 95% CI 1.11–1.71, P = 0.003). For those completing 12 weeks, FIB-4 > 3.25 and high BMI remained significant predictors.

Conclusions

In this robust real-world cohort, SVR rates were similar to clinical trials. FIB-4 > 3.25 and high BMI were significant negative predictors of SVR. Reduced odds of SVR in African Americans and with OPrD + RBV likely arose from excess early discontinuation as these factors were no longer
significant, when limited to patients completing a 12-week course.

Introduction

The landscape of antiviral therapy for chronic hepatitis C virus (HCV) infection continues to advance as all-oral options expand. Sustained virological response (SVR) rates reported in clinical trials with all-oral regimens are consistently above 90% for most HCV-infected patient populations and have become the expected norm. Because of the rapidity with which HCV therapies are progressing and the absence of comparative clinical trials, providers are left to extrapolate information to make clinical decisions about medication selection. Emerging real-world data of individual therapies have demonstrated results comparable to registration trials, however, comparative effectiveness evaluations are needed to determine whether clinical differences exist between regimens.[1-6] Comparative effectiveness analyses will become increasingly important as patients, providers, healthcare systems and managed care organisations consider additional nuances of convenience, drug interactions, treatment duration and ultimately cost effectiveness.

Ledipasvir/sofosbuvir (LDV/SOF) and ombitasvir/paritaprevir/ritonavir plus dasabuvir (OPrD) have been extensively evaluated individually in clinical trials of HCV-infected adults. The SVR rates in LDV/SOF trials of genotype 1 patients with and without cirrhosis ranged from 94% to 99% and in OPrD trials SVR rates ranged from 89% to 99%.[7-14] While these outcomes appear similar, differences in study design and patient populations prevent direct cross-study comparison of results.
Hepatitis C virus disproportionally affects the veteran population and the Department of Veterans Affairs (VA) is the largest US provider of healthcare to HCV-infected individuals caring for nearly 5% of all individuals in the US with HCV infection.[15, 16] Thus, ongoing evaluation of the effectiveness of HCV antiviral regimens remains a priority for VA.[17] With the rapid uptake of all-oral HCV regimens across the VA system and the diverse HCV-infected veteran population receiving these regimens, we examined SVR rates and comparative effectiveness of LDV/SOF ± ribavirin (RBV) vs. OPrD ± RBV in genotype 1 HCV-infected veterans treated in routine medical practice.

Materials and methods

This was an observational intent-to-treat cohort analysis of HCV-infected veterans receiving LDV/SOF ± RBV or OPrD ± RBV from VA. Data for this study were obtained from the VA's national Clinical Case Registry for HCV, an extract of the VA electronic medical record that contains demographics, laboratory results, pharmacy information and International Classification of Diseases diagnosis codes from inpatient hospitalisations, outpatient visits and problem lists of HCV-infected veterans seen at all VA medical facilities.[18]

Eligible subjects included all genotype 1 HCV-infected veterans from any VA facility nationwide who initiated 8 or 12 weeks of VA-prescribed LDV/SOF ± RBV or 12 weeks of OPrD ± RBV by 31 March 2015 with an end of treatment (EOT) by 14 July 2015 and a days supply less than or equal to 91 days. For patients who received multiple courses of therapy, only the first course was included. The choice of regimen and timing of follow-up visits and laboratory testing was at the discretion of the provider as patients were treated in routine practice. The present cohort includes 4356 treatment naïve patients treated with LDV/SOF ± RBV who were reported on previously.[19] Patients were excluded if they changed regimens without a treatment interruption (n = 64), had a baseline HCV RNA ≤1000 IU/mL (n = 218), had a liver transplant (n = 141), or had genotype subtype 1a and received OPrD without RBV (n = 16).

Treatment outcome

Patients were considered to have SVR if they had HCV RNA results below the limit of quantification on all HCV RNA tests after the EOT including at least one test 10 weeks or more after the EOT. The 10 week time point was chosen to account for variability of clinic visits and of laboratory testing draws in clinical practice. Patients were categorised as not achieving SVR if they had a HCV RNA above the limit of quantification after the EOT, had no HCV RNA testing after the EOT and a HCV RNA above the limit of quantification on their last HCV RNA test while on treatment or died while on treatment or within 10 weeks of the EOT. Patients with HCV RNA below the limit of quantification on their last HCV viral load test, either on treatment or after the EOT, but no test 10 weeks of more after the EOT were excluded from the SVR analysis. The EOT was calculated as the last day covered by prescriptions of LDV/SOF or OPrD using the dates the medication was dispensed and the days’ supply. HCV RNA was categorised as above or below the lower limit of quantification based on the locally reported HCV RNA result of which 98% utilised assays with a lower limit of quantification of 15 U/mL or less. Patients were followed from the initiation of LDV/SOF ± RBV or OPrD ± RBV through 29 February 2016, allowing for more than 32 weeks of follow-up after the EOT for all patients in the cohort.

Control variables

Demographic and other baseline variables were determined at the time of treatment initiation and included age, gender, race/ethnicity, diabetes, HIV coinfection, history of decompensated liver disease (defined by oesophageal variceal haemorrhage, hepatic coma, hepatorenal syndrome or spontaneous bacterial peritonitis), prescribed proton pump inhibitor use, prior HCV antiviral treatment experience and HCV genotype 1 subtype. Subtype 1a included patients with reported results of 1a, mixed 1a/1b or 1 with subtype unspecified. Prior virological response was based on the most recent VA course of HCV antiviral treatment and categorised as relapse, partial response, null response and not defined. Baseline values for height and weight used to calculate body mass index (BMI) and the laboratory tests for alanine aminotransferase, aspartate aminotransferase, platelets and baseline HCV RNA were defined as the value within 1 year before and closest to the treatment start date. A FIB-4 score >3.25 at the start of treatment using baseline laboratory values was used as a marker of advanced liver disease.[20, 21] Patients with FIB-4 ≤ 3.25 were considered to be ‘noncirrhotic’.

In VA, HCV antiviral prescriptions are frequently filled for quantities less than 28 days. Patients were considered to have completed 8 weeks of LDV/SOF if they had received between 49 and 63 days’ worth of medication and 12 weeks LDV/SOF ± RBV or OPrD ± RBV if they received between 77 and 91 days’ worth of medication.

Statistical analysis

Univariate comparisons used the Pearson chi-squared test with Yates’ continuity correction for categorical variables. Multivariate logistic regression models were constructed to model SVR. Models included age, gender, race/ethnicity, diabetes, history of decompensated liver disease, treatment experience, BMI, FIB-4, genotype 1 subtype, and regimen. In a sensitivity analysis proton pump inhibitor use was included in the model. A set of models with the above baseline variables was constructed with all patients and with only patients who completed 12 weeks of treatment.
For all comparisons, a P < 0.01 was considered statistically significant. All analyses were performed using R version 3.1 (R Foundation for Statistical Computing, Vienna, Austria).
The protocol was approved by the Stanford University Institutional Review Board and the VA Palo Alto Health Care System Research and Development Committee.

Results

In total, 6961 patients with HCV genotype 1 initiated LDV/SOF ± RBV (n = 5747) or OPrD ± RBV (n = 1214) at 126 VA facilities. The mean age for the cohort was 61.4 years, 96.3% were male, 36.0% were African-American, 31.5% had diabetes, 3.2% had a history of decompensated liver disease, 23.6% were treatment experienced, 35.4% had a BMI ≥30 kg/m², and 29.5% had a FIB-4 > 3.25.

Baseline characteristics for the cohort by regimen appear in Table 1. For the cohort, 64.3% (n = 4478) received LDV/SOF, 18.2% (n = 1269) received LDV/SOF + RBV, 4.3% (n = 297) received OPrD and 13.2% (n = 917) received OPrD + RBV. Patients who received LDV/SOF+RBV were most likely to be treatment-experienced and to have markers of advanced liver disease including a history of decompensated liver disease, lower mean platelet count, higher mean FIB-4 score, and FIB-4 > 3.25.

Table 1. Baseline characteristics and 4 week on-treatment response of genotype 1 patients receiving ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens with durations of 12 weeks or less

	Genotype 1 cohort (N = 6961)	LDV/SOF (N = 4478)	LDV/SOF + RBV (N = 1269)	OPrD (N = 297)	OPrD + RBV (N = 917)
Continuous variables reported as mean ± s.d. (range). Categorical variables reported as % (n). ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DAA, direct-acting antiviral; LDV/SOF, ledipasvir/sofosbuvir; OPrD, ombitasvir/paritaprevir/ritonavir + dasabuvir; PEG, pegylated interferon; SOF, sofosbuvir; RBV, ribavirin. *Some patients received more than one prior DAA regimen and are included in the count for each regimen they received.
Age (years)	61.4 ± 6.2 (24.5–90.8)	61.2 ± 6.5 (25.3–90.8)	61.9 ± 5.2 (24.5–86.2)	62.3 ± 5.9 (28.5–77.2)	61.5 ± 6.0 (26.7–85.3)
Gender, male	96.3 (6703)	95.9 (4295)	97.2 (1233)	96.3 (286)	96.9 (889)
Race/ethnicity
African-American	36.0 (2506)	38.2 (1712)	29.0 (368)	46.8 (139)	31.3 (287)
Caucasian	51.6 (3591)	50.5 (2263)	54.5 (692)	43.4 (129)	55.3 (507)
Hispanic	5.4 (376)	4.5 (304)	8.0 (102)	4.0 (12)	6.4 (59)
Other/multiple	7.0 (488)	6.7 (300)	8.4 (107)	5.7 (17)	7.0 (64)
Diabetes	31.5 (2195)	30.3 (1357)	37.7 (479)	33.3 (99)	28.4 (260)
Proton pump inhibitor	27.7 (1927)	26.3 (1178)	35.4 (449)	25.3 (75)	24.5 (225)
HIV coinfected	4.5 (310)	5.3 (237)	3.7 (47)	2.4 (7)	2.1 (19)
Decompensated liver disease	3.2 (224)	1.9 (87)	8.6 (109)	0.7 (2)	2.8 (26)
Any treatment experience	23.6 (1645)	16.0 (718)	53.0 (673)	19.2 (57)	21.5 (197)
DAA experience (% of treatment experienced)	44.1 (726)	39.1 (281)	62.4 (420)	7.0 (4)	10.7 (21)
Prior SOF + simeprevir (n)*	71	12	57	0	2
Prior SOF + PEG + RBV or SOF + RBV (n)*	131	29	96	0	6
Prior boceprevir (n)*	494	222	253	4	15
Prior telaprevir (n)*	74	21	53	0	0
Prior treatment response	N = 1645	N = 718	N = 673	N = 57	N = 197
Relapse	29.9 (492)	24.0 (172)	39.2 (264)	14.0 (8)	24.4 (48)
Partial	10.2 (167)	9.1 (65)	10.1 (68)	21.1 (12)	11.2 (22)
Null	11.3 (186)	9.6 (69)	11.1 (75)	12.3 (7)	17.8 (35)
Unknown	48.6 (800)	57.4 (412)	39.5 (266)	52.6 (30)	46.7 (92)
BMI (kg/m2)	28.8 ± 5.3 (15.8–65.2)	28.5 ± 5.2 (15.8–65.2)	30.0 ± 5.5 (16.4–60.1)	28.2 ± 5.0 (16.0–53.7)	28.8 ± 5.3 (17.6–58.5)
BMI (kg/m2)
<25	23.1 (1605)	24.8 (1109)	17.9 (227)	24.2 (72)	21.5 (197)
25–29	41.6 (2893)	41.6 (1863)	37.6 (477)	49.8 (148)	44.2 (405)
≥30	35.4 (2463)	33.6 (1506)	44.5 (565)	25.9 (77)	34.4 (315)
ALT (U/L)	74.1 ± 56.5 (8–659)	71.4 ± 55.9 (8–659)	80.3 ± 52.3 (13–445)	62.6 ± 50.7 (13–552)	82.4 ± 64.3 (11–560)
AST (U/L)	64.4 ± 45.5 (6–614)	60.5 ± 43 (6–614)	76.6 ± 48.2 (11–503)	50.6 ± 34.8 (14–322)	70.4 ± 52.1 (13–499)
Platelets (Κ/μL)	185.6 ± 69.9 (6–759)	194.4 ± 68.2 (6–661)	150.3 ± 67.9 (22–759)	214.6 ± 59.6 (81–421)	181.8 ± 66.7 (32–470)
FIB-4	3.2 ± 3.7 (0.1–185.0)	2.8 ± 3.8 (0.1–185.0)	4.7 ± 4.1 (0.5–34.7)	2.0 ± 1.2 (0.3–10.0)	3.3 ± 2.9 (0.4–27.3)
FIB-4	N = 6936	N = 4460	N = 1267	N = 296	N = 913
≤3.25	70.5 (4889)	76.4 (3406)	47.8 (605)	89.5 (265)	67.1 (613)
>3.25	29.5 (2047)	23.6 (1054)	52.2 (662)	10.5 (31)	32.9 (300)
HCV RNA (log IU/mL)	6.2 ± 0.7 (3.0–7.9)	6.2 ± 0.7 (3.1–7.9)	6.2 ± 0.7 (3.0–7.8)	6.3 ± 0.6 (3.9–7.6)	6.3 ± 0.7 (3.0–7.8)
HCV RNA (IU/mL)
<6 000 000	82.0 (5705)	82.7 (3705)	84.6 (1073)	76.8 (228)	76.2 (699)
≥6 000 000	18.0 (1256)	17.3 (773)	15.4 (196)	23.2 (69)	23.8 (218)
HCV subtype 1b	27.3 (1897)	24.2 (1085)	23.4 (297)	100.0 (297)	23.8 (218)
IL28B polymorphism	N = 989	N = 598	N = 204	N = 33	N = 154
CC	20.3 (201)	22.6 (135)	15.2 (31)	9.1 (3)	20.8 (32)
CT	54.0 (534)	52.7 (315)	58.3 (119)	51.5 (17)	53.9 (83)
TT	25.7 (254)	24.7 (148)	26.5 (54)	39.4 (13)	25.3 (39)

Among patients who received LDV/SOF, 3.6% (n = 159) discontinued treatment before 8 weeks, 32.7% (n = 1464) received 8 weeks, 1.7% (n = 77) discontinued treatment between 8 and 12 weeks and 62.0% (n = 2778) received 12 weeks. In total, 94.7% completed either an 8 or 12 week course. Among people who received LDV/SOF + RBV, 8.1% (103/1269) discontinued treatment prior to completing 12 weeks. Among patients who received OPrD or OPrD+RBV, 11.4% (34/297) and 15.2% (140/917) of patients, respectively, discontinued treatment prior to completing a 12 week course. Significantly more patients receiving OPrD + RBV discontinued treatment prior to completing a 12-week course compared to those receiving LDV/SOF + RBV (P < 0.001).

Sustained virological response results were available for 94.0% (n = 6542) of patients in the cohort, including 24 patients who died while on treatment or shortly after who were categorised as no SVR. Four hundred nineteen patients whose last HCV RNA was undetectable, but occurred while still on treatment (n = 123) or less than 10 weeks after the EOT (n = 296), were excluded from the SVR analysis. Three hundred five patients had an undetectable HCV RNA obtained 10–11 weeks after the EOT and were included in the SVR analysis for reasons described previously.

Among 4170 LDV/SOF patients 91.4% achieved SVR; among 1220 LDV/SOF + RBV patients 90.0% achieved SVR; among 283 OPrD patients 95.1% achieved SVR and among 869 OPrD + RBV patients 85.8% achieved SVR (Table 2). For patients who received LDV/SOF, the SVR rates differed statistically based on categories of race/ethnicity, BMI, and FIB-4. For patients who received LDV/SOF + RBV, the SVR rates differed statistically based on proton pump inhibitor use and FIB-4. No statistically significant differences in SVR were observed according to baseline patient characteristics among patients receiving either OPrD or OPrD + RBV, and responses were generally similar to that observed in the overall population. SVR data for treatment naïve and experienced patients by subgroup can be found in Table S1A and B.

(Table 2).  SVR rates by regimen for genotype 1 patients receiving ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens with durations of 12 weeks or less

Click On Image To Enlarge

For patients who completed an 8 week course of LDV/SOF or a 12 week course of LDV/SOF ± RBV or OPrD ± RBV, SVR rates were consistently higher overall and among subgroups when compared to the intention-to-treat SVR rates (Table 3). With regard to the impact of treatment duration among patients who received LDV/SOF, the SVR rate in those who received 8 weeks was 91.7% (1223/1333) and 94.6% (2475/2615) in those who received 12 weeks. An SVR rate of 92.2% (1033/1120) was achieved in patients completing 12 weeks of LDV/SOF + RBV and 95.5% (705/738) in those completing 12 weeks of OPrD+RBV. In genotype 1b patients who received 12 weeks of OPrD, an SVR rate of 98.0% (248/253) was achieved. In 1098 patients who met the Food and Drug Administration (FDA) labelling considerations for a shortened LDV/SOF course consisting of treatment-naïve, without cirrhosis (defined as FIB-4 ≤ 3.25), and a baseline HCV RNA <6 000 000 IU/mL and who completed 8 weeks of LDV/SOF therapy, the SVR rate was 93.2% (1023/1098). In 905 patients who also met the FDA considerations for a shortened LDV/SOF course but nevertheless received 12 weeks of LDV/SOF therapy, the SVR rate was 96.6% (874/905)(P = 0.001 compared to 8 week course).

Table 3. SVR rates by regimen for genotype 1 patients receiving ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens who received 8 or 12 weeks of LDV/SOF and 12 weeks of all other regimens

Click On Image To Enlarge

In multivariate analysis, significant independent predictors of decreased odds of SVR were African American race (OR 0.71, 95% CI 0.59–0.86, P < 0.001), BMI ≥30 kg/m² (OR 0.73, 95% CI 0.60–0.89, P = 0.002), FIB-4 > 3.25 (OR 0.60, 95% CI 0.49–0.72, P < 0.001) and use of OPrD + RBV compared to LDV/SOF (OR 0.60, 95% CI 0.48–0.76, P < 0.001) (Table 4). Genotype subtype 1b was an independent predictor of increased odds of SVR (OR 1.38, 95% CI 1.11–1.71, P = 0.003). Age, gender, diabetes, history of decompensated liver disease and treatment experience did not predict SVR. In the sensitivity analysis proton pump inhibitor use was not associated with a difference in the odds of achieving SVR (0.85, 95% CI 0.71–1.03, P = 0.09). In models limited to patients receiving 12 weeks of treatment, only BMI ≥30 kg/m² (OR 0.66, 95% CI 0.49–0.88, P = 0.004) and FIB4 > 3.25 remained significant (OR 0.46, 95% CI 0.35–0.60, P < 0.001).

Table 4. Odds ratios for sustained virological response in multivariate model for genotype 1 patients treated with ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens

	Intention-to-treat OR (95% CI), N = 6525	Received 12 weeks OR (95% CI), N = 4720
BMI, body mass index; CI, confidence interval; LDV/SOF, ledipasvir/sofosbuvir; OPrD, ombitasvir/paritaprevir/ritonavir+dasabuvir; OR, odds ratio; RBV, ribavirin; ref., reference; SVR, sustained virological response. †Subtype 1a includes 1a, mixed 1a/1b and 1 with subtype unspecified. **P < 0.01, ***P < 0.001.
Age <55 years (ref. 55–64)	1.37 (0.98–1.94)	1.36 (0.83–2.37)
Age ≥65 years (ref. 55–64)	1.17 (0.96–1.43)	1.26 (0.94–1.70)
Female (ref. Male)	2.23 (1.26–4.38)	2.51 (1.04–8.23)
African American (ref. Caucasian)	0.71 (0.59–0.86)***	0.86 (0.64–1.14)
Hispanic (ref. Caucasian)	0.77 (0.54–1.12)	1.00 (0.59–1.81)
Other/multiple (ref. Caucasian)	0.87 (0.62–1.23)	0.81 (0.51–1.34)
Diabetes (ref. no diabetes)	1.01 (0.83–1.22)	1.08 (0.82–1.42)
Decompensated liver disease (ref. no)	0.60 (0.41–0.90)	0.87 (0.51–1.54)
Treatment experienced (ref. naïve)	0.90 (0.73–1.11)	0.90 (0.67–1.21)
BMI <25 kg/m2 (ref. 25–29 kg/m2)	0.77 (0.61–0.96)	0.99 (0.69–1.44)
BMI ≥30 kg/m2 (ref. 25–29 kg/m2)	0.73 (0.60–0.89)**	0.66 (0.49–0.88)**
FIB-4 > 3.25 (ref. ≤3.25)	0.60 (0.49–0.72)***	0.46 (0.35–0.60)***
HCV subtype 1b (ref. 1a†)	1.38 (1.11–1.71)**	1.44 (1.04–2.02)
LDV/SOF + RBV (ref. LDV/SOF)	1.07 (0.84–1.37)	0.87 (0.64–1.19)
OPrD (ref. LDV/SOF)	1.27 (0.74–2.37)	1.68 (0.71–4.93)
OPrD+RBV (ref. LDV/SOF)	0.60 (0.48–0.76)***	1.22 (0.83–1.84)

Discussion

In this robust comparative effectiveness analysis of LDV/SOF ± RBV vs. OPrD ± RBV in genotype 1 HCV-infected veterans treated in routine medical practice, high SVR rates were achieved overall (86–95%) and within subgroups (83–100%). In multivariate models, OPrD + RBV was found to be less effective than LDV/SOF and patients receiving the former were 40% less likely to achieve SVR. However, in patients who completed a 12-week treatment course there was no difference in effectiveness. Similar to clinical trials, curative all-oral treatment has become a reality for over 90% of patients treated in the real-world, even in those with characteristics previously associated with poorer outcomes. This analysis demonstrates the real-world comparative effectiveness of all-oral DAA regimens in individuals with genotype 1 HCV infection that clinicians, patients and payers have anticipated.

The current HCV treatment landscape remains complex despite increasingly more effective HCV regimens, with variability in outcomes for patients with previous treatment experience, genotype subtype, race, degree of underlying liver disease and other comorbid conditions.[7, 8, 13, 14, 22-24] Because of the large sample size in this cohort, we were able to do robust subgroup analyses to examine differences among these characteristics and identify where challenges remain.
Despite SVR rates higher than any previously reported among veterans with advanced liver disease, the presence of advanced liver disease as indicated by a FIB-4 score greater than 3.25 remained a significant negative predictor of response with an apparent impact for treatment naïve and treatment experienced patients and across all regimens.[5, 23, 25] Over 2000 patients with advanced liver disease were included in this cohort. In multivariate models, the presence of advanced liver disease predicted reduced odds of achieving SVR by 40% independent of treatment experience and regimen. Absolute SVR rates in treatment naïve patients were generally four to five percent lower in those with advanced liver disease compared to those without advanced liver disease for patients who received LDV/SOF (87.6% vs. 92.6%), who received LDV/SOF + RBV (90.0% vs. 94.7%), and who received OPrD (91.7% vs. 96.1%). Current AASLD/IDSA treatment guidelines and FDA labelling recommend LDV/SOF for 12 weeks in treatment naïve patients with cirrhosis based largely on data from 34 patients in the ION-1 trial.[7, 26, 27] However, our observation of SVR rate of 87.6% with LDV/SOF in 889 treatment naïve patients with FIB4 scores >3.25 indicate SVR rates with this regimen may be below the 90% bar for which all-oral regimen expectations have been set and other treatment options might need to be considered in such patients.

In treatment experienced patients with and without advanced liver disease, reductions of 5–8% in SVR rates were seen in patients who received LDV/SOF (85.5% vs. 93.5%), who received LDV/SOF + RBV (85.4% vs. 90.9%), and who received OPrD + RBV (82.1% vs. 89.6%). The reduced SVR rates in the low to mid-80s in treatment experienced patients with advanced liver disease in this study mirror the 86% and 82% SVR rates observed in ION-2 in treatment-experienced cirrhotic patients receiving 12 weeks of LDV/SOF and LDV/SOF + RBV respectively.[8] In the TURQUOISE-II study SVR rates were 87% and 95% in treatment experienced cirrhotic null responders treated for 12 and 24 weeks respectively with OPrD+RBV.[14] The large number of patients included in our study coupled with the similar results obtained from ION-2 and TURQUOISE-II suggest that lower SVR rates may be expected in cirrhotic patients and particularly treatment-experienced cirrhotic patients treated in routine clinical practice. Extended treatment of 24 weeks in such patients may be warranted to achieve higher SVR rates.

In this cohort, SVR data were available for over 2300 African Americans. Multivariate modelling indicated African American race was associated with a 29% reduction in the odds of SVR. This effect was observed in multivariate models of the overall cohort but not in models limited to patients completing a 12 week treatment course suggesting that the reduced odds of SVR for African Americans arose in large part from excess early treatment discontinuations and from diminished effectiveness of 8-week LDV/SOF in African Americans, which has also been observed in retrospective analyses of the ION clinical trials.[22] Numerically lower SVR rates were observed in African Americans compared to Caucasians treated with LDV/SOF, OPrD and OPrD+RBV. In patients who received a full 12 weeks of treatment, SVR rates in African Americans were higher than in the intention-to-treat analysis and the numeric differences in SVR rates between African Americans and Caucasians were diminished.

This study included over 2300 patients with a BMI at or above 30 kg/m², and in the overall cohort those with high BMI were 27% less likely to achieve SVR. As one might expect, the effect of BMI on SVR was not dependent on whether the patient completed therapy and, as such, high BMI remained a negative predictor of response in those who completed a 12-week treatment course. For such patients, additional treatment options may need to be considered to optimise SVR rates.
Shorter 8 week regimens were widely used in treatment-naïve patients with baseline HCV RNA below 6 000 000 IU/mL without cirrhosis. We could only assess the use of 8 week LDV/SOF regimens in patients who completed therapy because we were unable to otherwise determine if the original provider intent was to treat for 8 or 12 weeks using the available electronic data. Although the difference in SVR rates between those who completed 8 weeks and those who completed 12 weeks was numerically small at 3.4% it was statistically significant suggesting that to optimise a patient's likelihood of SVR the 12-week duration may be preferred.

Real-world SVR rates achieved with these treatment regimens were remarkably high. The large differences between real-world effectiveness and clinical trial efficacy previously observed with HCV antiviral treatment have now been almost eliminated with the use of potent all-oral regimens. Most of the small decrement in observed effectiveness in this real-world cohort may be explained in large part by higher early discontinuation rates. Early discontinuations rates were highest in those receiving OPrD + RBV (15.2%), followed by OPrD (11.4%), LDV/SOF + RBV (8.1%) and LDV/SOF (5.3%). Clinical trials tend to have early discontinuation rates of less than 3%.[7-14] Higher early discontinuation rates had the greatest impact on SVR rates in those receiving OPrD + RBV with a nearly 10% difference in SVR rates comparing intention-to-treat (85.8%) to those who completed 12 weeks (95.5%). While we did not examine reasons for early discontinuation, adverse effects and adherence are often recognised as contributing factors. Setting appropriate expectations about potential medication side effects and continued emphasis on adherence and persistence will remain important elements in maximising treatment success. Any remaining decrement in clinical effectiveness compared to clinical trial efficacy may be explained by differences in patient populations. For example, higher BMI in our cohort was identified as a significant negative predictor of SVR.

Given the high SVR rates achieved in clinical practice even among subgroups, regimen selection will depend increasingly upon nuanced considerations. Genotype subtype, presence of cirrhosis, prior treatment regimen or presence of pre-existing resistance associated polymorphisms currently determines the need for RBV and subsequent length of treatment for certain regimens. Potential for drug interactions and comorbidities may limit use of a particular agent. Enough options presently exist to allow providers some flexibility in selecting regimens tailored to meet individual patient characteristics or needs without sacrificing effectiveness. Expectations for high SVRs have been set and now validated in real-world cohorts, thus regimen subtleties together with cost considerations and insurance coverage will be key determinants for utilisation.

While this study includes one of the largest cohorts of diverse HCV-infected patients treated in clinical practice published to date, there are limitations. Specific reasons for early discontinuation (i.e. adverse events, poor tolerability, social or behavioural issues) could not be determined from the electronic data. Duration of treatment and early treatment discontinuation rates were determined based on the cumulative dispensed days’ supply which may overestimate the treatment duration as patients may have discontinued treatment even with medication in their possession. In VA, many prescriptions are filled for small quantities (e.g. 2-week supplies) which would limit the extent of the overestimation. Baseline resistance testing was not performed thus we were unable to assess the impact of this factor.

Conclusions

In this large real-world cohort of genotype 1 HCV-infected veterans treated with LDV/SOF-based or OPrD-based therapy, high SVR rates comparable to clinical trials were observed and were consistently high across all subgroups evaluated. Odds of SVR were reduced in African Americans compared to Caucasians, those receiving OPrD + RBV compared to LDV/SOF, those with advanced liver disease and those with BMI ≥30 kg/m² compared to those with lower BMI. Reduced odds of SVR for African Americans and those receiving OPrD + RBV arose in large part from early discontinuation as these predictors no longer had a significant impact on odds of SVR in those who completed a 12-week course. Advanced liver disease and higher BMI, however, persisted as significant negative predictors of SVR even when considering only those patients who completed a 12-week course. For patients with advanced liver disease and high BMI longer durations of therapy or additional treatment options may still be needed to increase SVR rates. Real-world experience from large diverse cohorts such as this is necessary to better inform and refine HCV management strategies.

Authorship

Guarantor of the article: Lisa I. Backus.
Author contributions: Drs Backus, Belperio, Loomis and Mole: Study concept and design. Drs Backus, Belperio, Shahoumian, Loomis and Mole: Analysis and interpretation of data; Drs Backus, Belperio: drafting of the manuscript, Drs Backus, Belperio and Mole: Critical revision of the manuscript for important intellectual content; Dr Shahoumian: Statistical analysis. This statement acknowledges that all authors approved the final version of the article, including the authorship list.

Acknowledgement

Declaration of personal and financial interests: None.

Source http://onlinelibrary.wiley.com/enhanced/doi/10.1111/apt.13696

Survival rates rise with new hepatitis C treatments

Survival rates rise with new hepatitis C treatments

Just a few years ago the outlook for treating patients with chronic hepatitis C was grim.

For almost a year, patients would receive a complicated regimen of shots and up to 18 pills a day with drugs that caused major side effects. After that, there was a six-month follow-up period to see if the treatment was successful.

And the cure rate was less than 50 percent.

Thanks to recent research ― some of it conducted in San Antonio ― most patients now can be cured with direct-acting antivirals, a gentler combination of drugs in one or a few pills with only a few months of treatment. Continuing research is promising for new treatments for the groups of patients who don’t respond well to the new standard therapy.

“The good news is patients should know that a paradigm shift has occurred as we now can give all-oral therapy that is simple, safe and highly effective with cure rates of about 95 percent for most patient populations,” said Dr. Eric Lawitz, professor in the School of Medicine at the UT Health Science Center San Antonio.

Lawitz and Dr. Fred Poordad, also a professor of medicine at the UT Health Science Center, see patients at the Texas Liver Institute in San Antonio. They have been researching cures for hepatitis C for years with great success. They have presented oral presentations at international liver meetings and published peer-reviewed articles in major journals that have changed the standard of care for patients.

The FDA-approved drugs they have evaluated include Harvoni (a combination of ledipasvir and sofosbuvir), Olysio (simeprevir), Viekira Pak (ombitasvir, paritaprevir and ritonavir packaged with dasabuvir tablets), Zepatier (elbasvir and grazoprevir) and Daklinza (daclatasvir).

‘Silent epidemic’
The tragedy of hepatitis C is that is that it has no symptoms until the disease progresses, so patients can have the disease for many years and not know it.

“For that reason it is often called a silent epidemic,” Poordad said. “If not identified early, the disease can progress to cirrhosis of the liver, liver cancer and the need for a liver transplant. And even if the patient receives a liver transplant, the disease must be cured or it can infect the new liver 

What causes hepatitis C?
According to the Centers for Disease Control, hepatitis C is the leading blood-borne disease in the U.S. Although some people have only a mild form of the disease, 75 percent to 85 percent of patients who become infected with the hepatitis C virus will develop a chronic infection. This is estimated to be more than 3.5 million people in the nation.

The virus spreads through contact with the blood of an infected person. This often occurs through sharing needles, syringes or other equipment used in drug use. Another common way is through needle-stick injuries in a health-care setting. Mothers with hepatitis C can pass the disease on to their unborn children. Less common ways of spreading the virus are by sharing toothbrushes and razors, or by having sexual contact with a person who has hepatitis C. Some people contracted the disease years ago through blood transfusions before widespread screening of the blood supply began in 1992.

Find out if you have hepatitis C
According to the CDC, baby boomers ― people born between 1945 and 1965 ― are five times more likely to be infected with hepatitis C than other adults. “You can find out if you have hepatitis C through a simple blood test at your doctor’s office. All you have to do is request it,” Poordad said.

More information about hepatitis C, the blood test for the virus, and the newest treatments are available at the CDC website, www.cdc.gov.

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Blood-born molecules could predict those who will develop liver cancer

Blood-born molecules could predict those who will develop liver cancer

(PHILADELPHIA) - Hepatocellular carcinoma, the most common type of liver cancer, is increasing in incidence in the United States, and infection with the Hepatitis B virus (HBV) causes about 50 percent of cases. However, it can be difficult to identify who is most likely to develop this cancer. Although earlier research had discovered molecular signatures associated with HBV-driven liver cancer, new research from Thomas Jefferson University has proven that this panel of microRNAs can also predict the patients at high risk for developing the disease before the cancer develops, via a blood test.

The researchers, led by Hushan Yang, Ph.D., an Associate Professor of Medical Oncology and researcher at the Sidney Kimmel Cancer Center at Jefferson studied a large cohort of HBV-infected patients, some of whom eventually developed liver cancer, and analyzed their molecular signature from blood samples. Of the 373 HBV patients who were originally cancer free, 40 developed cancer over a median follow up of 4.5 years. The researchers analyzed a panel of 24 microRNAs -- small molecules that regulate gene activity -- and showed that 15 of these microRNAs had changed their normal gene expression pattern before patients developed cancer, suggesting these molecules could be used to predict patients with a high likelihood of developing cancer. The study was published in the journal Oncotarget,

Earlier studies had identified the 24 microRNAs that Dr. Yang and colleagues studied. However, it was unclear whether those microRNAs caused the cancer, or were a result of already occurring cancerous processes. By following this cohort of patients prospectively, and using blood samples taken at least one year before liver cancer diagnosis, the researchers were able to answer that question for the first time. In addition, prior studies analyzed samples taken from patient biopsies, which require invasive procedures, whereas the current study showed that microRNAs circulating in the blood could predict disease.

"This research confirms previous work on microRNAs and liver cancer and goes further to show that these microRNAs may be able to predict the development of liver cancer through a non-invasive blood test," says first author Chun Wang, a visiting scholar in the Department of Medical Oncology.

The current non-invasive test for determining cancer risk among HBV patients is a diagnostic for the molecule alpha-fetoprotein (AFP). It is also associated with Hepatitis C infections, but it isn't always a good predictor of disease. In fact, the Jefferson researchers identified 15 out of 16 patients, or 94 percent of patients who were misclassified as cancer-free by AFP. Likewise, in the 57 patients who were deemed at high risk of developing liver cancer by AFP, the microRNA testing correctly reclassified 33, or 58 percent, as low risk.

Although the panel of 15 microRNAs was useful, it wasn't perfect. "We need to find more microRNAs that may predict liver cancer in order to sharpen this tool for identifying high risk patients," says Dr. Yang. "Through collaboration with Dr. Hann in the Department of Medicine at Jefferson, we continue to work on improving this diagnostic method."

The work was supported by a Tobacco Grant from the Pennsylvania Department of Health, National Cancer Institute Grant CA159047, American Cancer Society Research Scholar Grant 123741-RSG-13-003-01-CCE, and a V Scholar Grant from the V Foundation for Cancer Research. The authors report no conflicts of interest.

Source: Thomas Jefferson University