hCV

Hepatitis C Drug Sofosbuvir Still Effective at 24 Weeks.

Posted by

0


New data from 4 phase 3 trials with the hepatitis C (HCV) drug sofosbuvir (SOF) and ribavirin (RBV) show that a 12-week regimen is effective in treating HCV genotypes 1 through 6. Twenty-four-week sustained virologic response (SVR) is essentially identical to 12-week SVR, bolstering confidence that the drug combination represents a cure. Those with genotype 3 infections are better served with a 16-week course of treatment.

The new work extends the results of the studies out to 24 weeks after treatment cessation. Twenty-four weeks was the traditional milestone for HCV treatments, but in recent years, the US Food and Drug Administration and industry have gravitated toward the 12-week time point. However, with new drugs set to greatly affect HCV treatment, it is important to consider this older benchmark, according to Kris Kowdley, MD, director of the Liver Center of Excellence at the Digestive Disease Institute at the Virginia Mason Medical Center in Seattle, Washington, who presented the research here at the American College of Gastroenterology (ACG) 2013 Annual Scientific Meeting and Postgraduate Course.

“We’re in a brave new world of hepatitis C treatments, and we’re very quickly reaching all oral, interferon-free, short-duration regimens, so I think it remains valuable to continue following patients to 24 weeks, and possibly 48 weeks, posttreatment to see if the assumption [of a cure] really holds up. We can also learn more about late relapses and possible questions about resistance,” Dr. Kowdley told Medscape Medical News.

The research drew from 4 phase 3 studies: Sofosbuvir With Peginterferon Alfa 2a and Ribavirin for 12 Weeks in Treatment-Naive Subjects With Chronic Genotype 1, 4, 5, or 6 HCV Infection (NEUTRINO), which enrolled treatment-naive patients with genotype (GT) 1, 4, 5, and 6 infection, each of whom received 12 weeks of SOF, peg-interferon (PEG), and ribavirin (RBV); Phase 3 Study of Sofosbuvir and Ribavirin (FISSION), which enrolled treatment-naive GT 2/3 patients to receive either 12 weeks of SOF+RBV or 24 weeks of PEG+RBV; GS-7977 + Ribavirin for 12 Weeks in Subjects With Chronic Genotype 2 or 3 HCV Infection Who Are Interferon Intolerant, Interferon Ineligible or Unwilling to Take Interferon (POSITRON), which enrolled GT 2/3 patients unable or unwilling to receive interferon, who were randomly assigned to receive 12 weeks of SOF+RBV or placebo; and Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection (FUSION), which enrolled treatment-experienced GT2/3 patients who received 12 or 16 weeks of SOF+RBV.

For all studies, the primary end point was sustained virologic response (HCV RNA < 25 IU/mL) at 12 weeks posttreatment (SVR12).

In the studies, participants had a mean age of 53 years (range, 19 – 77 years) and a mean body mass index of 28 kg/m2 (range, 17 – 56 kg/m2). Demographics were consistent with those of the HCV-infected population in the United States. Six percent of the participants were receiving opioid replacement therapy.

Table 1. 12-Week SVR Rates

GT 1,4,5,6 GT 2 and 3
NEUTRINO FISSION POSITRON FUSION
SOF/PEG/RBV (n = 327) SOF/RBV (n = 253) PEG/RBV (n = 243) SOF/RBV (n = 207) Placebo (n = 71) SOF/RBV 12 week (n = 100) SOF/RBV 16 week (n = 95)
Overall 91% 67% 67% 78% 0% 50% 73%
GT 2 N/A 97% 78% 93% 0% 86% 94%
GT 3 N/A 56% 63% 61% 0% 30% 62%
Noncirrhotic 93% 72% 74% 81% 0% 61% 76%
Cirrhotic 80% 47% 38% 61% 0% 31% 66%

Compensated cirrhosis at baseline was found in 17% of patients in the NEUTRINO study, 21% in FISSION, 18% in POSITRON, and 33% in FUSION.

In all studies, SVR12 was higher in patients without cirrhosis. Patients with GT 2 experienced higher SVR12 rates than those with GT 3.

SVR 24 rates were similar to SVR 12 rates.

Table 2. SVR12 vs SVR24

SVR12 SVR24
Treatment-naïve patients
GT 1, 4, 5, 6 overall 91% 91%
GT 1 90% 90%
GT 4 96% 96%
GT 5 and GT 6 100% 100%
Treatment-naive and experienced GT 2, 3 patients
Treatment-naive 67% 67%
Interferon unable 78% 78%
Previously treated (12 week regimen) 51% 50%
Previously treated (16 week regimen) 73% 72%

The additional data back up the 12-week SVR. “In all the studies, the 24-week results are almost identical [to the 12-week SVR]. We detected durability of that response,” said Dr. Kowdley. The studies also suggest that interferon is not needed to achieve SVR in genotypes 2 and 3, although Dr. Kowdley said that trials of interferon-sparing regimens are underway.

The results further underscore the anticipation that physicians have toward sofosbuvir and other new drugs. “I think 2 years ago there was a standing-room only meeting in San Francisco, where Pharmasset (which originally developed sofosbuvir), dropped just unbelievable results, and we all thought this was too good to be true,” Tim Little, MD, a physician with Puget Sound Gastroenterology in Seattle, Washington, who attended the presentation, told Medscape Medical News.

“I don’t know that there’s anything incredibly new about (this study), but it’s confirmation that this dramatic result that this very small group of investigators presented is actually real, and I think we can all understand that this is as good as they said it was going to be, or almost as good,” Dr. Little said.

On October 25, an FDA advisory committee unanimously recommended approval of sofosbuvir based on the 12-week results. The FDA is expected to make a decision by December 8.

Source: American College of Gastroenterology (ACG)

Human Breast Milk Inactivates Hepatitis C Virus Infectivity.

Posted by

0


 A new study shows why breastfeeding is generally safe even when mothers are infected with the hepatitis C virus (HCV).

The reason is that human breast milk inactivates hepatitis C virus (HCV) infectivity by disrupting its envelope, researchers from Germany have found.

“This study provides a novel mechanism for the protective properties of human mother’s milk against HCV,” Dr. Eike Steinmann from the TWINCORE Center for Experimental and Clinical Infection Research in Hannover told Reuters Health by email. “A new finding is that lipases in human milk generate free fatty acids that damage the viral envelope and render them non-infectious.”

In an editorial published with the paper online September 24 in The Journal of Infectious Diseases, Dr. Ravi Jhaveri from the University of North Carolina in Chapel Hill says “the results provide a plausible explanation for why breastfeeding is not a risk factor for HCV transmission. This is reassuring for us as practitioners when we counsel our HCV patients that it is safe for them to breastfeed.”

Using breast milk from healthy HCV-negative women, the research team found that even short preincubation periods of HCV in the milk brought consistent reductions of HCV infectivity by 2 to 3 orders of magnitude.

The breast milk inactivated HCV infectivity independent of the viral genotype, and antiviral activity was concentration dependent. Concentrations between 4% and 6% milk were sufficient to reduce HCV infectivity, whereas higher dilutions abolished the antiviral effect.

The antiviral activity was specific to human milk. It was not found in milk from horses, cows, or commercial infant formula.

The anti-viral activity was not destroyed by heat treatment, the authors reported.

In a series of experiments, the researchers showed that lipases in human milk generated fatty acids that disrupted the viral envelope, resulting in the loss of viral infectivity.

“Similar processes concerning the release of free fatty acids take place upon digestion of human breast milk by the infant,” the investigators note. “Therefore, milk digestion products, like free fatty acids, released in the stomach might be able to inactivate residual viral particles which otherwise could be transmitted upon breastfeeding.”

Human breast milk also had significant antiviral effects against other enveloped viruses (influenza, herpes simplex, and vesicular stomatitis virus) but no pronounced effect on non-enveloped viruses (murine norovirus, rotavirus).

“As there are far more enveloped viruses known than tested in this study, further investigations are necessary,” Dr. Steinmann said.

“Human breast milk efficiently inactivates HCV in vitro and neither the Centers for Disease Control nor the American Association for the Study of Liver Diseases argues against breastfeeding from HCV infected women unless they have cracked or bleeding nipples,” Dr. Steinmann concluded.

Dr. Jhaveri’s editorial concludes, “After reading this article, when we clinicians next encounter an HCV infected patient that just delivered a healthy infant and wants to breastfeed, we have yet another reason to say ‘Breast is Best.'”

Interferon-Free Regimen for HCV Genotype 1 Infection: Closer Still.

Posted by

0


Despite promising findings, including higher response rates with inclusion of ribavirin in a triple-therapy regimen, response rates are still too low in this group to forgo interferon.
Interferon-free regimens should be available soon for hepatitis C virus (HCV) genotype 2 infection and probably genotype 3 infection. For now, the next-generation regimen for genotype 1 infection will be shorter and more tolerable but will still include interferon.

To continue the search for an effective, interferon-free regimen for HCV genotype 1 infection, researchers conducted an industry-funded, multicenter, randomized, open-label, phase IIb study in 362 treatment-naive patients. Patients received faldaprevir (120 mg once daily) plus deleobuvir (600 mg 2 or 3 times daily) with or without ribavirin (1000–1200 mg daily) for 16, 28, or 40 weeks. The primary endpoint was sustained virologic response at 12 weeks posttreatment (SVR12).

SVR12 did not differ by treatment duration (16 weeks, 59%; 28 weeks, 59%; 40 weeks, 52%) or by deleobuvir dose (69% for twice daily and 59% for three times daily). SVR12 was higher in ribavirin users versus nonusers (59% vs. 39%, P=0.03). SVR12 rates were numerically higher in patients with genotype 1b versus 1a (range across treatment groups, 56% to 85% vs. 11% to 47%) and in patients with IL28B genotype CC versus non-CC (range across treatment groups, 58% to 84% vs. 33% to 64%). Of 75 patients with virologic breakthrough, 73 had resistant HCV variant strains. Discontinuation rates ranged from 5% to 25% across treatment groups; the most common adverse events were rash, photosensitivity, nausea, vomiting, and diarrhea.

COMMENT

We are getting closer to an interferon-free regimen for genotype 1 hepatitis C virus infection, but we are not there yet. Ribavirin will likely still be needed as a part of the regimen. Also, multiple interferon-free regimens might be required, with choice of regimen based on predictors of response such as genotype 1 subtype and IL28B status. Finally, until their sustained virologic response rates approach 80%, interferon-free regimens will likely only be an option for patients for whom interferon-based regimens are intolerable or contraindicated.

 Source: NEJM

USPSTF Recommends Hepatitis C Screening for High-Risk Adults, Baby Boomers.

Posted by

0


High-risk adults, including injection drug users and those who received blood transfusions before 1992, should be screened for hepatitis C virus, according to new guidelines from the U.S. Preventive Services Task Force in the Annals of Internal Medicine. In addition, adults born from 1945 through 1965 (so-called baby boomers) should undergo one-time screening.

The USPSTF says anti-HCV antibody testing, followed by confirmatory polymerase chain reaction, is accurate for detection.

The guidance is an update from the task force’s 2004 statement, which found insufficient evidence for or against screening in high-risk patients. The CDC has recommended screening for high-risk adults since 1998, and recommended one-time screening for baby boomers last year.

Editorialists write: “The independently derived yet similar recommendations for HCV testing from the USPSTF and CDC send a clear signal to health care professionals … that screening for HCV is effective.”

Source: Annals of Internal Medicine 

Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial.

Posted by

0


Summary

Background

Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1—3 HCV infection.

Methods

In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1—3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18—70 years, had an HCV RNA concentration of 50 000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 μg per week) and ribavirin (1000—1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772.

Findings

In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events—fatigue, headache, nausea, and chills—were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77—97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80—98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37—77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12.

Interpretation

Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1.

Source: Lancet

Treatment of HCV Infection by Targeting MicroRNA

Posted by

0


BACKGROUND

The stability and propagation of hepatitis C virus (HCV) is dependent on a functional interaction between the HCV genome and liver-expressed microRNA-122 (miR-122). Miravirsen is a locked nucleic acid–modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function.

METHODS

In this phase 2a study at seven international sites, we evaluated the safety and efficacy of miravirsen in 36 patients with chronic HCV genotype 1 infection. The patients were randomly assigned to receive five weekly subcutaneous injections of miravirsen at doses of 3 mg, 5 mg, or 7 mg per kilogram of body weight or placebo over a 29-day period. They were followed until 18 weeks after randomization.

RESULTS

Miravirsen resulted in a dose-dependent reduction in HCV RNA levels that endured beyond the end of active therapy. In the miravirsen groups, the mean maximum reduction in HCV RNA level (log10 IU per milliliter) from baseline was 1.2 (P=0.01) for patients receiving 3 mg per kilogram, 2.9 (P=0.003) for those receiving 5 mg per kilogram, and 3.0 (P=0.002) for those receiving 7 mg per kilogram, as compared with a reduction of 0.4 in the placebo group. During 14 weeks of follow-up after treatment, HCV RNA was not detected in one patient in the 5-mg group and in four patients in the 7-mg group. We observed no dose-limiting adverse events and no escape mutations in the miR-122 binding sites of the HCV genome.

CONCLUSIONS

The use of miravirsen in patients with chronic HCV genotype 1 infection showed prolonged dose-dependent reductions in HCV RNA levels without evidence of viral resistance.

Source: NEJM

 

 

Next-Generation Protease Inhibitor Effective for HCV Infection.

Posted by

0


Patients who received vaniprevir achieved higher rapid virologic response rates than those who received placebo.

Adding telaprevir and boceprevir to standard peginterferon and ribavirin therapy has been shown to significantly improve virologic response rates for patients with genotype 1 hepatitis C virus (HCV) infection (JW Gastroenterol Jul 1 2011 and JW Gastroenterol Mar 30 2011). However, these first-generation HCV nonstructured protein (NS)3/4A protease inhibitors require a complex administration schedule and are associated with additional adverse effects.

To evaluate the efficacy and safety of vaniprevir (MK-7009) — a macrocyclic next-generation HCV NS3/4A protease inhibitor that is administered once or twice daily — investigators conducted an industry-funded, phase II, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study involving 94 treatment-naive adults with chronic HCV genotype 1 infection. Patients were assigned to vaniprevir (300 mg twice daily, 600 mg twice daily, 600 mg daily, or 800 mg daily) or matched placebo in combination with peginterferon (180 μg weekly) and ribavirin (1000–1200 mg daily) for 4 weeks. Thereafter, all patients continued peginterferon and ribavirin for 44 weeks. The primary endpoint was rapid virologic response (RVR); exploratory endpoints included sustained virologic response (SVR).

All 94 patients completed the 4-week triple-dosing regimen. Of these, 78 completed 48 weeks of peginterferon and ribavirin treatment, and 84 completed a 6-month post-therapy follow-up. The rate of viral decline by week 4 was at least 3log10 IU/mL greater in the vaniprevir groups versus the placebo group. Rates of RVR were significantly higher in all vaniprevir groups versus the placebo group (68.8%–83.3% vs. 5.6%; P<0.001). SVR rates were nonsignificantly higher in the vaniprevir groups than the placebo group (61.1%–84.2% and 63.2%, respectively), likely due to the small sample size. Safety profiles were similar between the vaniprevir and placebo groups, except vomiting occurred more often in the vaniprevir groups. HCV resistance variants were noted in three patients receiving vaniprevir.

Comment: This phase II study of vaniprevir shows early promise for a next-generation protease inhibitor–based triple therapy that is easy to administer in a daily or twice-daily dosing schedule. Subsequent vaniprevir studies are needed to identify the optimal dose and duration of therapy to maximize SVR and maintain an excellent safety profile.

Source: Journal Watch Gastroenterolog

 

Hepatocellular Carcinoma: Consensus Recommendations of the National Cancer Institute Clinical Trials Planning Meeting

Posted by

0


Hepatocelluar carcinoma (HCC) is the most common primary malignancy of the liver in adults and the third most common cause of cancer death worldwide. The incidence of HCC in the United States is rising steadily because of the prevalence of hepatitis C viral infection and other causes of hepatic cirrhosis. The majority of patients have underlying hepatic dysfunction, which complicates patient management and the search for safe and effective therapies. The Clinical Trials Planning Meeting (CTPM) in HCC was convened by the National Cancer Institute’s Gastrointestinal Cancer Steering Committee to identify the key knowledge gaps in HCC and define clinical research priorities. The CTPM structured its review according to current evidence-based treatment modalities in HCC and prioritized the recommendations on the basis of the patient populations representing the greatest unmet medical need.

source:JCO

Hepatitis C Virus Transmission at an Endoscopy Clinic

Posted by

0


Eight cases were identified; contamination and reuse of open propofol vials was the likely source.

Hepatitis C is the most common bloodborne infection in the U.S. Although nosocomial transmission of hepatitis C virus (HCV) is considered rare, the number of cases associated with nonhospital medical settings is increasing. Now, researchers describe an outbreak of HCV infection at an endoscopy clinic.

During a 5-week period in 2007, three patients developed acute hepatitis after undergoing endoscopy at a single clinic in Las Vegas. Among the 123 additional patients who underwent endoscopy at that clinic on the same dates as these individuals, 6 were known to be HCV infected and were considered potential source patients; the remaining 117 were advised to undergo screening for antibodies to HCV. This testing identified an additional five patients who met the case definition for clinic-acquired HCV infection.

Genetic analysis of the HCV from the eight patients with clinic-acquired infections and from the six patients known to have been infected before their procedures allowed the identification of the source patient for each endoscopy date. Among HCV-susceptible individuals who underwent endoscopy after the source patients, HCV infection developed in 1 of 49 (2%) whose procedures occurred on the first date and in 7 of 38 (18%) whose procedures occurred on the second date. During the investigation, an anesthetist was observed placing a new needle on a syringe, then refilling the syringe from a propofol vial that was intended for single use but had been used for other patients.

Comment: This outbreak of HCV infection was likely related to contamination of open propofol vials through refilling of syringes that had become contaminated with the source patients’ blood. This practice was routine in the clinic, so it is surprising that more infections did not occur.

— Neil M. Ampel, MD

Published in Journal Watch Infectious Diseases July 21, 2010