Publishing their findings in the journal eLife, researchers screened for pathogens among samples taken from the teeth of 53 excavated skeletons dating from Neolithic and medieval sites in Germany. The individuals whose remains were found lived from about 5000 BC to 1200 AD.

The investigators recovered the full hep B genomes from three samples, two of which were from about 7,000 and 5,000 years ago—the oldest HBV genomes recovered to date—and the other from the medieval period.

Compared with modern strains of the virus, the hep B strains found in the two Stone Age samples were relatively similar to each other. These samples were also similar to HBV that is found in chimpanzees and gorillas in the present day. The virus found in the medieval sample was more similar to modern human strains of hep B. Previously discovered virus samples from 16thcentury mummies were also similar to modern human strains.

It appears that the strain of the virus seen in the Stone Age samples may have gone extinct.

Together, these findings suggest that hep B has remained relatively stable over the past 500 years and that over the previous millennia, the virus may have crossed over from primates to human multiple times.

“Antiviral therapy can reduce not only hepatic manifestations of HCV but also many extrahepatic manifestations related to HCV when SVR is achieved,” said Dr. Patrice Cacoub from Hopital La Pitie-Salpetriere in Paris.

“Such findings reinforce the importance (of diagnosing and treating) early all HCV infected patients to avoid hepatic and extrahepatic complications,” he told Reuters Health by email.

As many as two-thirds of patients with chronic HCV infection develop extrahepatic manifestations, which have been shown to play a role in HCV mortality.

Dr. Cacoub and colleagues undertook a systematic review and meta-analysis of 48 studies to assess the impact of achieving SVR after antiviral treatment on the extrahepatic morbidity and mortality in patients with the disease.

Achievement of SVR was associated with a 56% reduction in the odds of extrahepatic mortality (odds ratio, 0.44; 95% confidence interval, 0.28 to 0.67), they report in Gut, online April 27.

SVR achievement was also associated with a 20.76-fold increase in the odds of complete remission and a 27.24-fold increase in the odds of improvement of cryoglobulinemic vasculitis, a 6.49-fold increase in the odds of objective response of lymphoproliferative diseases, as well as a 58% reduction in the odds of insulin resistance in patients without diabetes and a 66% reduction in the odds of diabetes at follow-up. All these findings were statistically significant.

The odds of major adverse cardiovascular events declined by 63% after SVR achievement, the odds of ischemic events declined by 30% and the odds of experiencing renal events declined by 85%. These differences were also significant.

Fatigue scores declined after achieving SVR, but there was no significant reduction in the presence of depression after SVR achievement.

“Higher quality data, and reporting over longer follow-up periods, will be required to thoroughly explore comprehensive HCV treatment strategies,” the researchers conclude.

Dr. Nancy S. Reau from Rush University Medical Center, in Chicago, who recently reviewed the economic burden of extrahepatic manifestations of HCV, told Reuters Health by email, “Multiple health conditions (including all-cause mortality) have been linked to HCV. Viral eradication may have a strong impact in reducing a wide array of complications.”

“We can view this two ways,” she said. “The obvious is that therapy should be prioritized in patients with extrahepatic manifestations. This supports the recommendations in the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines. The other is that SVR may prevent non-liver associated complications.”

Gilead supported this work through an unrestricted grant, and two of the four authors had ties to the company, which makes drugs for viral hepatitis.

Source: https://www.medscape.com/viewarticle/896909

“[Antiviral therapy] for HCV infection is beneficial for patients with HCV-associated mixed cryoglobulinemia or indolent [non-Hodgkin lymphomas (NHLs)], as they can have complete resolution of symptoms of cryoglobulinemia and lymphoma regression,” Parag Mahale, PhD, MPH, from the National Cancer Institute, Maryland, and colleagues wrote. “However, this risk reduction was not observed when [antiviral therapy] was started 2 or more years after the HCV index date.”

Mahale and colleagues retrospectively reviewed the data of 160,875 adults with HCV from the Veterans Affairs HCV Clinical Case Registry, most of whom were men (97.1%), aged between 50 years and 59 years (52.1%), and had genotype 1 (54.7%). Approximately 19% of the patients received antiviral therapy, 34% of whom achieved SVR.

Most extrahepatic manifestations had an incidence rate less than 1 per 1,000 person-years, including mixed cryoglobulinemia, porphyria cutanea tarda (PCT), lichen planus, NHL and coronary heart disease; whereas glomerulonephritis, diabetes and stroke occurred more frequently in all three patient groups: untreated, treated without SVR and treated with SVR. Glomerulonephritis, diabetes and stroke occurred less frequently in patients who achieved SVR compared with treated patients without SVR.

Multivariate analysis showed that patients who achieved SVR had significantly lower risks for mixed cryoglobulinemia (HR = 0.61; 95% CI, 0.39-0.94), glomerulonephritis (HR = 0.62; 95% CI, 0.48-0.79), PCT (HR = 0.41; 95% CI, 0.2-0.83), NHL (HR = 0.64; 95% CI, 0.43-0.95), diabetes (HR = 0.82; 95% CI, 0.76-0.88) and stroke (HR = 0.84; 95% CI, 0.74-0.94) compared with untreated patients.

Among those who did not achieve SVR, the risks for glomerulonephritis (HR = 0.82; 95% CI, 0.69-0.96) and stroke (HR = 0.82; 95% CI, 0.75-0.9) decreased significantly, while the risks for lichen planus (HR = 1.56; 95% CI, 1.22-1.99) and diabetes (HR = 1.14; 95% CI, 1.08-1.2) increased significantly.

Finally, the researchers restricted analysis to treated patients and found that patients who achieved SVR had a lower risk for mixed cryoglobulinemia (HR = 0.55; 95% CI, 0.33-0.9), glomerulonephritis (HR = 0.75; 95% CI, 0.57-0.99), PCT (HR = 0.31; 95% CI, 0.14-0.65) and diabetes (HR = 0.72; 95% CI, 0.65-0.78) compared with those without SVR.

The researchers observed gradual reductions in significance of antiviral treatment with increasing time from HCV index date for glomerulonephritis, NHL and stroke. Antiviral therapy showed the most significant protection when initiated at 1 or 2 years after HCV index date for glomerulonephritis and stroke, and at 1 year for NHL.

“These findings further strengthen the epidemiological evidence for [extrahepatic manifestations’] association with HCV infection,” the researchers concluded. “HCV-related [extrahepatic manifestations] carry a significant economic burden due to direct medical costs and indirect costs due to loss of productivity. The results of our study emphasize the extrahepatic benefits of SVR.” – by Talitha Bennett

Disclosure: Mahale reports no relevant financial disclosures. Please see the full study for the other authors’ relevant financial disclosures.

Source: healio.com

Jonas Söderholm, PhD, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden, and colleagues found that 2.5% of approximately 45,000 patients with HCV developed chronic kidney disease compared to 0.7% in a matched comparator population, and that HCV further increased the risk of kidney failure requiring hemodialysis.

The researchers also found, however, that DAA treatment of the HCV approximately doubled the survival rate of patients on hemodialysis with 24% mortality, compared to 56% mortality in patients with untreated HCV.

“Chronic infection with HCV can be both a cause and a potential complication of kidney disease,” Söderholm and colleagues explained. “With an extended follow-up, we showed that HCV treatment improved survival for patients with chronic hepatitis C infection before and during hemodialysis compared with untreated patients.”

Although there has previously been evidence that HCV infection increases risk for developing chronic kidney disease, and that DAA treatment of HCV can produce a sustained virologic response (SVR) equivalent to cure, Söderholm and colleagues pointed out that DAA treatment has been underutilized in the patients who require hemodialysis.

They attribute the infrequent treatment of HCV in these patients, in part, to the adverse effects associated with the older regimens of interferon with or without ribavirin. In addition, Söderholm and colleagues indicate, the initially available DAA, sofosbuvir (Sovaldi), is renally excreted, and its safety had not been fully assessed in patients with renal failure.

According to a large international observational study, only 1% of patients with HCV infection on hemodialysis received any antiviral treatment prior to introduction of the DAAs. In a subsequent study conducted between 2012-2105, after the introduction of DAAs, only 2.1% of hemodialysis patients with HCV received antiviral treatment.

Söderholm and colleagues emphasized that DAA treatment continues to be underutilized in these patients despite availability of several sofosbuvir-free DAA regimens, which have been found both effective and well tolerated in patients on hemodialysis. Examples of these are dasabuvir, ombitasvir/parpitaprevir/ritonavir (ViekiraXR) with and without ribavirin, and elbasvir/grazoprevir (Zepatier) and glecaprevir/pibrentasvir (Mavyret).

“The most striking finding of the present study is the significant survival benefit of treating HCV in patients with chronic hepatitis C infection on hemodialysis,” Söderholm and colleagues indicated, “and that this benefit remained significant after controlling for age, acute kidney failure diagnosis, and kidney transplantation.”

In an accompanying editorial, Richard Moreau, MD, Division of Researchers, National (French) Institute of Health (INSERM), and colleagues underscored the importance of acting on this finding.

“The clear message from this nationwide cohort study is to prioritise interferon-free treatment in HCV-infected patients with chronic kidney disease with or without hemodialysis,” researchers wrote.

Source: mdmag.com

Previous research indicated that compared with interferon-based treatment, direct-acting antiviral treatment raised this risk.

Contrary to the findings of previous research, a new study has found that compared with receiving interferon-based treatment for hepatitis C virus (HCV), curative interferon-free direct-acting antiviral (DAA) therapy is not associated with an increased risk of developing hepatocellular carcinoma (HCC, the most common form of liver cancer) among people with cirrhosis, MedPage Today reports.

Publishing their findings in the Journal of Hepatology, researchers analyzed data on 857 people cured of hep C between 1997 and 2016. They all had been diagnosed with cirrhosis, none had yet been diagnosed with liver cancer and none were coinfected with hepatitis B virus (HBV) or HIV.

This study was initially presented at the 52nd International Liver Congress in Amsterdam in April 2017.

During a median follow-up of 2.4 years, the study population was diagnosed with liver cancer at an overall rate of 1.45 diagnoses per 100 cumulative years of follow-up. During a median 1.7 years of follow-up among those who received interferon-based treatment, 12 individuals were diagnosed with the cancer, for a rate of 1.7 diagnoses per 100 cumulative years of follow-up. And during a median 3.5 years of follow-up among those who were treated with interferon-free DAA regimens, 34 people were diagnosed with the cancer, for a diagnosis rate of 2.53 per 100 cumulative years of follow-up.

These findings meant that, at first glance, it seemed that interferon-free DAA treatment was associated with a higher risk of developing liver cancer following being cured of hep C, specifically a 2.48-fold elevated risk compared with receiving interferon-based treatment.

However, the researchers found that other baseline factors (meaning characteristics specific to the individuals at the beginning of the study’s follow-up period) were also associated with an increased risk of post–hep C cure liver cancer diagnosis, including: being older, as individuals in their 50s and those age 60 and older were a respective 2.75-fold and 3.31-fold more likely to be diagnosed with liver cancer than those in their 40s; having a Child-Turcotte-Pugh score (an indication of the severity of liver disease, on a scale of A to C, with A being the least severe) of B, compared with A (a 5.24-fold greater risk); having low platelets (3.96-fold increased risk); and having been treated for hep C two or more previous times (3.52-fold increased risk).

After the study authors adjusted the data to account for differences among the study cohort members according to that list of risk factors, they found that there was no statistically significant difference in the liver cancer diagnosis rate between those treated with and without interferon, meaning that any apparent difference (a 1.15-fold increased risk for those who received interferon-free treatment) may have been driven by chance.

A recent study analyzed health outcomes among those with decompensated cirrhosis treated with Sovaldi-based regimens.

A newly developed scoring system can help predict whether individuals with decompensated cirrhosis (the more severe form of the advanced liver disease) will see their liver damage dial back after being cured of hepatitis C virus (HCV).

Publishing their findings in the journal Gastroenterology, researchers analyzed data on 622 people with advanced liver disease who were treated for hep C with Sovaldi (sofosbuvir)-based regimens in the SOLAR-1, SOLAR-2, ASTRAL-4 and GS-US-334-0125 clinical trials. A total of 502 of these individuals had Child-Pugh Turcotte class B liver disease and 120 had class C liver disease.

According to the Child-Pugh Turcotte scoring system, those with class A, B and C have an expected one-year survival rate of 100 percent, 81 percent and 45 percent, respectively, and an expected two-year survival rate of 85 percent, 57 percent and 35 percent.

Before treatment, 77 percent of the study cohort had ascites (the abnormal buildup of fluid in the abdomen) and 77 percent had mild encephalopathy (the loss of brain function driven by a compromised liver failing to remove toxins from the blood).

Eighty-five percent of the study cohort achieved a sustained virologic response 12 weeks after completing therapy (SVR12, considered a cure). Seventeen people received liver transplants, and 35 individuals died during follow-up.

Of the 528 individuals who were cured of hep C and had 36 weeks of follow-up, 31.6 percent of those who started treatment with Child-Pugh Turcotte class B liver disease saw a reduction to class A, as did 12.3 percent of those who initially had class C.

Factors associated with a lower chance of a reduction in Child-Pugh Turcotte liver disease class included a higher body mass index (BMI), encephalopathy, ascites and an albumin level less than 3.5 grams per deciliter.

The study authors created a scoring system they called BE3A in which five factors were each assigned one point, including: not having encephalopathy, not having ascites, having an ALT enzyme level higher than 60 international units per liter and having an albumin level higher than 3.5 g/dL.

A score of 4 or 5 according to the BE3A points system was associated with a 75 percent likelihood of regressing to class A liver disease, while those with a score of 1 had just a 25 percent chance of such liver disease regression. Having any score between 1 and 5 did not predict whether individuals would undergo liver transplant or die during follow-up, but a BE3A score of 0 was associated with a 25 percent chance of either of those outcomes.

Highlights

Among those for whom treatment with AbbVie’s Mavyret (glecaprevir/pibrentasvir) did not cure their hepatitis C virus (HCV) after the first go-round, intensifying the regimen by retreating with Mavyret plus Sovaldi and ribavirin yields a high cure rate.

Preliminary findings from an ongoing study of individuals who experienced virologic failure after Mavyret treatment were presented at the 2018 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.

The study includes individuals who participated in AbbVie’s Phase IIIb clinical trials of Mavyret experienced virologic failure, including eight people from SURVEYOR-2, eight from ENDURANCE-3, six from MAGELLAN-1 and one from EXPEDITION-1.

Individuals who had genotypes 1, 2, 4, 5 or 6 of hep C, did not have cirrhosis and were not treated with a NS5A inhibitor or protease inhibitor before taking Mavyret the first time were assigned to receive 12 weeks of Mavyret plus Sovaldi and ribavirin. The two people who fell into this category had genotype 2 and had a mutation in their virus associated with resistance to the NS5A inhibitor class of direct-acting antivirals (DAAs) for HCV.

The remaining 21 people were treated for 16 weeks, a treatment length assigned to those with genotype 3, those who had cirrhosis, and those who were previously treated with an NS5A inhibitor or protease inhibitor. Seven of the individuals treated for 16 weeks had genotype 1; 14 of them had genotype 3. Seven had compensated cirrhosis (the milder form of the advanced liver disease) and six had been treated with an NS5A inhibitor prior to their initial Mavyret treatment. Sixteen of these individuals had a viral mutation associated with NS5A inhibitor resistance, five of them also had a mutation linked to resistance to NS3/4A inhibitor DAAs.

The study excluded those coinfected with hepatitis B virus (HBV) and those with decompensated cirrhosis, the more severe stage of the advanced form of liver disease. The trial did not exclude those coinfected with HIV, although such individuals had to be either off antiretroviral treatment for that virus or on ARVs with a fully suppressed viral load.

Both of the participants who were treated for 12 weeks achieved a sustained virologic response 12 weeks after completing therapy (SVR12, considered a cure). Ninety-five percent (20 of 21) of those treated for 16 weeks were cured. The one person in the study who did not achieve an SVR12 experienced virologic failure following the intensified regimen had genotype 1a, compensated cirrhosis and had not been cured by Harvoni (ledipasvir/sofosbuvir) prior to taking Mavyret the first time.

No participant experienced a serious adverse health event judged related to treatment. A total of 82.6 percent experienced any adverse health event, including headache (26.1 percent of participants), itching (21.7 percent), dizziness (17.4 percent), irritability (17.4 percent), fatigue (13 percent), insomnia (13 percent) and upper respiratory-tract infection (13 percent).

One person (4.3 percent of the total group) experienced a lab-based abnormality.

“Monotherapy with [pegylated-interferon alpha 2b] or tenofovir has limited efficacy in HBeAg positive chronic hepatitis B. Combination therapy with [pegylated-interferon alpha 2b] and tenofovir may improve serological response rates,” Ankur Jindal, MD, MBBS, from the Institute of Liver and Biliary Sciences, India, and colleagues wrote. “Viral load reduction followed by immune modulation is a potentially useful approach. This approach may reduce the relapse, increase off-treatment response and may therefore facilitate the discontinuation of [nucleos(t)ide analogues].”

The study comprised 53 patients who received tenofovir monotherapy and 53 patients who received tenofovir with pegylated-interferon alpha 2b added from 12 weeks to 36 weeks, after which all patients continued tenofovir monotherapy until end of follow-up at 72 weeks. One patient from each group discontinued before end of follow-up.

At end of the follow-up, significantly more patients who received pegylated-interferon alpha 2b reached the primary endpoint of HBeAg loss (35.8% vs. 17%; OR = 2.73; 95% CI, 1.09-6.79). However, no patient in either group achieved HBeAg seroreversion.

Rates of HBV DNA loss (77.4% vs. 71.7%), alanine aminotransferase normalization (62.3% vs. 52.8%) and sustained virological response (20.8% vs. 11.3%) were comparable between the two groups at 72 weeks.

At 36 weeks, however, significantly more patients who received pegylated-interferon alpha 2b had more than 3 log HBV DNA reduction (92.5% vs. 66%; P = .001) and pegylated-interferon alpha 2b correlated significantly with HBeAg loss at 72 weeks (OR = 0.36; 95% CI, 0.15-0.91).

At 72 weeks, three patients who received pegylated-interferon alpha 2b achieved HBsAg loss and one of those achieved HBsAg seroconversion. None of the patients on tenofovir monotherapy achieved significant HBsAg loss.

Combined pegylated-interferon alpha 2b and tenofovir therapy was generally well tolerated. Adverse effects occurred most frequently among those with pegylated-interferon alpha 2b combined therapy, though the cumulative frequency of reported adverse events was comparable at 72 weeks.

“As high viral load in [chronic hepatitis B] leads to impaired T-cell responsiveness to various HBV proteins, a 12-week short course of tenofovir before add-on [pegylated-interferon alpha 2b] therapy restores the specific T-cell responsiveness by reducing the HBV load resulting in higher frequency of HBeAg loss and SVR,” the researchers concluded. “Further studies are required to identify if this sequential therapy would allow more patients to achieve and sustain HBsAg loss.” – by Talitha Bennett

Under the terms of the collaboration announced at the 18th International Congress on Infectious Diseases (ICID), Buenos Aires, Egyptian pharmaceutical company Pharco Pharmaceuticals (Pharco) will supply the active pharmaceutical ingredients for sofosbuvir and drug candidate ravidasvir. Pharmaceutical company Insud Pharma and Argentinian research and development company Laboratorio Elea Phoenix (Elea) will register, manufacture, and distribute ravidasvir and sofosbuvir in Latin America. Non-profit research and development organization Drugs for Neglected Diseases initiative (DNDi) will collaborate with clinical trials data and jointly with non-profit foundation Mundo Sano will collaborate on advocacy activities to boost access to easy diagnosis and affordable treatment of hepatitis C virus (HCV).

“Our ambition is to help develop a new safe, effective, and affordable treatment regimen which will allow countries to take a public health approach to hepatitis C,” said Dr Bernard Pécoul, DNDi Executive Director.

Currently a 12-week course of HCV treatment is available in Argentina for at least US$7,000, in Chile for $12,000 and in Brazil for over $6,000. Although the cost of manufacturing ravidasvir is potentially higher than some direct-acting antivirals (DAAs), the commitment from all partners to a reasonable profit margin means that the target price of the new ravidasvir/sofosbuvir combination will be under $500 in Latin America.

“We are proud to have Insud Pharma, Elea, and Pharco as reliable industrial partners capable of registering and manufacturing what will be a quality new drug that could transform the dynamic of access to HCV treatment in Latin America,” said Silvia Gold, President of Mundo Sano.

Ravidasvir is an NS5A inhibitor produced by Pharco, one of a new generation of DAAs that are revolutionizing the treatment of hepatitis C. DNDi clinical trials are testing its potential use as a treatment in combination with sofosbuvir, an existing DAA, to prove its pan genotypic profile in treatment-naïve and treatment-experienced patients, in cirrhotic and non-cirrhotic patients, in people co-infected with both HCV and HIV, and in people who inject drugs. The full safety and efficacy results of a Phase II/III clinical trial in 301 patients in Malaysia and Thailand, covering the same genotypes as are prevalent in Latin America, will be published in April 2018. In an earlier Phase III clinical trial in 300 patients in Egypt, conducted by Pharco, ravidasvir showed an overall cure rate of 98% in patients with genotype 4 when used in combination with sofosbuvir.

“We hope that our collaboration will lead to widespread access to safe, effective, and affordable treatment for patients in Argentina and around the region,” said Dr Sherine Helmy, CEO of Pharco Pharmaceuticals.

“As a leading Argentine pharmaceutical company, one of Elea’s principles is the development of new effective, safe, and affordable therapies for people. This new treatment will be fully produced in our manufacturing facilities in Argentina and will be available for all those living with this disease in Argentina and Latin America,” said Eduardo Spitzer, Scientific Director, Elea Phoenix.

Countries in the region are adopting different strategies to face the high price of HCV treatment. However, a number of patent applications that could prevent affordable access to sofosbuvir are pending in Argentina and in other Latin American countries, all of which are middle-income countries (MIC) as per the World Bank’s classification. In September 2017, Malaysia, also an MIC, issued a “government use” licence enabling access to more affordable versions of the expensive medicine. This landmark decision will help the more than 400,000 people living with hepatitis C in Malaysia access sofosbuvir, and could have important repercussions in the global effort to secure access to treatments for this viral disease.