HCV Combo Works Without Old Standbys

Published: Jan 16, 2014

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

• Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3.
• The combination worked equally well with or without ribavirin.

Chronic hepatitis C (HCV) can be treated effectively without any of the standard drugs, researchers reported.

In an open-label study, all-oral combination therapy yielded cure rates ranging from 89% to 100% depending on patient and treatment characteristics, according to Mark Sulkowski, MD, of Johns Hopkins University, and colleagues.

Importantly, the combination of daclatasvir and sofosbuvir (Sovaldi)worked equally well with or without ribavirin, one of the mainstays of HCV therapy for years, Sulkowski and colleagues reported in the Jan. 16 issue of the New England Journal of Medicine.

The combination also worked equally well regardless of previous treatment failure, the presence of mutations associated with poor response to therapy, and viral genotypes regarded as difficult to treat, the investigators reported.

For years, chronic HCV was treated with pegylated interferon, an injectable drug with a host of difficult and dangerous side effects, and ribavirin, an oral drug with its own suite of hazards including hemolytic anemia and teratogenicity.

Therapy was usually protracted and cure rates -- sustained virologic responses (SVR), defined as no detectable HCV at a given point after the end of treatment -- were low.

The addition of drugs that block the HCV protease enzyme has improved outcomes, but clinicians and patients have been waiting for all-oral regimens that eliminate both interferon and ribavirin.

"In my view," Sulkowski told MedPage Today by email, "this clinical trial demonstrates the potential for interferon-free and ribavirin-free regimens for persons infected with HCV genotype 1."

In the trial, patients with genotypes 1, 2, or 3 of the virus were given daclatasvir/sofosbuvir, with or without ribavirin, for 12 or 24 weeks.

The primary endpoint -- reached by 201 of 211 patients -- was a sustained virologic response 12 weeks after the end of therapy, or SVR₁₂.

SVR₁₂ rates were:

• 98% in previously untreated genotype 1 patients and the same in genotype 1 patients who had failed previous therapy with interferon, ribavirin, and HCV protease inhibitors
• 92% of patients with genotype 2, and 89% of those with genotype 3 infection
• 98% and 100%, respectively, among patients with HCV subtypes 1a and 1b
• 93% and 98%, respectively, for those with CC and non-CC IL28B genotypes, where the non-CC genotypes are regarded as predicting poor response
• 94% among those who also got ribavirin, and 98% among those who did not

The study heralds an "exciting time for HCV treating physicians," commented Paul Pockros, MD, of the Scripps Clinic in La Jolla, Calif., who was not part of the study.

"We can cure most patients finally," he told MedPage Today by email.

Whether those cures will come from the daclatasvir/sofosbuvir combination, however, is an open question.

As data from this trial was revealed at successive medical meetings, Pockros and others hailed the outcomes as a "home run" for HCV treatment.

Fears for the Future

But there were fears it would be a strikeout for patients -- the two drugs are owned by different companies and were being tested under a collaborative agreement that has now ended.

Among other things, that means the drugs are unlikely to be co-formulated as a single pill or approved as a combination with a broad indication.

But Sulkowski noted that three phase III trials have been registered, although they are not yet recruiting, for relatively narrow indications -- genotype 3 patients, those with concurrent HIV, and people with cirrhosis or recurrent HCV after liver transplant.

The two drugs are so-called direct-acting anti-virals -- they target aspects of the virus itself, rather than boosting the immune system as interferon does.

Daclatasvir blocks the action of the viral NS5A replication complex, while sofosbuvir, approved last year, is a nucleotide analog NS5B polymerase inhibitor.

Both of the companies involved in the trial -- Bristol-Myers Squibb with daclatasvir and Gilead with sofosbuvir -- have their own versions of the other's medication.

Gilead is testing the combination of sofosbuvir and ledipasvir, its own NS5A inhibitor. BMS is testing triple therapy with daclatasvir, an NS5B blocker dubbed BMS-791325, and asunaprevir, a protease inhibitor.

But if daclatasvir is approved on its own, Pockros said, it's likely some doctors at least will prescribe it with sofosbuvir off label.

Indeed, the two most recently approved HCV drugs are sofosbuvir and the protease inhibitor simeprevir (Olysio) -- neither indicated for use with the other.

But, Pockros said, they are being widely used together based on data from a clinical trial that has been reported but not yet published.

"Support for the (daclatasvir/sofosbuvir) regimen will be even firmer," he said, although it's not clear how gladly insurers would support such use.

A Practice-Changing Regimen?

The bottom line, Sulkowski said, is that the study suggests that the combination -- or one using similar medications -- has the potential to make an important impact on HCV therapy.

"The combination of an NS5A inhibitor and an NS5B inhibitor was associated with high cure rates in a range of HCV-infected patients," he and colleagues argued.

A separate open-label phase 2b study in the journal evaluated triple or quadruple drug regimens given for eight, 12, or 24 weeks in a cohort of 571 patients divided into 14 treatment subgroups.

The research groups overlapped -- Sulkowski, for instance, was part of both studies -- but with the exception of ribavirin, none of the drugs, all direct-acting anti-virals, were the same.

The primary analysis was the rate of SVR₂₄ among treatment-naive patients who got three direct-acting agents plus ribavirin for eight weeks, compared with those who got the same therapy for 12 weeks, according to Kris Kowdley, MD, of Virginia Mason Medical Center in Seattle, and colleagues.

Kowdley and colleagues studied the HCV protease inhibitor ABT-450 boosted with ritonavir, the non-nucleoside polymerase inhibitor ABT-333, the NS5A inhibitor ABT-267, and ribavirin in patients with genotype 1 infection.

The key finding, they reported, was that 88% of those who got eight weeks of therapy and 95% of those who got 12 weeks reached an SVR₂₄.

The seven percentage-point difference was not statistically significant, the researchers reported.

Over all treatment groups, SVR₂₄ rates ranged from 83% to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia.

The study by Sulkowksi and colleagues was supported by Bristol-Myers Squibb and Pharmasset (Gilead). Sulkowski reported financial links with the companies, as well as Novartis, Janssen, Vertex, BIPI, Abbott, Merck, Roche/Genentech, BIPI, and Pfizer.

The study by Kowdley and colleagues was supported by AbbVie. Kowdley reported financial links with the company, as well as with Boehringer Ingelheim, BMS, Gilead/Pharmasset, Intercept, Janssen, Merck, Mochida, Vertex, and Novartis.

Pockros has reported financial links with Novartis, Tibotec, GlobeImmune, Genentech, Merck, BMS, Gilead, Vertex, Three Rivers Pharmaceuticals, Debio, Pfizer, Conatus Pharmaceuticals, Abbott, and Mochida Pharmaceuticals.

Primary source: New England Journal of Medicine
Source reference: Sulkowski MS, et al "Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection" N Engl J Med 2014; 370: 211-221.

Additional source: New England Journal of Medicine
Source reference:Kowdley KV, et al "Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1" N Engl J Med 2014; 370: 222-232.

Source

HCV: who/how to screen - HCV is a Disease of the Marginalized

from Jules Levin, NATAP

READ THE NUMBERS. THE MARGINALIZED populations estimated to have HCV make up a LARGER proportion than you think. If you read the articles/reports in these links you will see the disproportionate affect of HCV in marginalized patient populations. If you closely look at the data on who has HCV, the new NHANES survey just published linked to below, and then compare that to the large prevalence of HCV in the marginalized communities, it is clear that these marginalized communities are more key & need special attention including because they are harder to reach but also because numerically they are more critical than you think. I think a larger focus for awareness, linkage to care & care must be on marginalized populations if we are to hope to uncover all those with us diagnosed HCV. The 1.5-2% prevalence in the general population in the USA referred to in the new NHANES report below is likely an overestimate for the impact on individuals not a member of these identified marginalized populations, so this says screening and awareness projects need to focus and target on these marginalized pops! This changes the thinking regarding how to diagnose the undiagonsed! what methods to use! it's not just about general awareness. We need targeted outreach awareness & screening based on patient group characteristics: homeless, IDUs, prisoners, Latinos, African-Americans, immigrants (Russians, Indian peninsula, East Asia etc), which will bring increased effectiveness, support programs are necessary to achieve ultimate success of cure, i.e. linkage to care, treatment support. In marginalized communities (IDUs, African-Americans, Latinos) many do not know where to go for screening so what is needed is culturally appropriate awareness telling people exactly where to go for screening, then you need direct linkage to care, preferably with an on-site case mgr, because it is too often too difficult for many of these individuals to navigate the healthcare system, many of them are alienated from the healthcare system, they may not have ever been to a doctor or very infrequent, often he healthcare system is not friendly to them. Then of course for certain IDU populations and other marginalized patient populations you need care situations in which they feel comfortable, that welcomes them & works for their situations. The HCV affected populations are very segmented & awareness/outreach programs need to be very much tailored to them specifically based on culture, neighborhood, and life-experiences. General awareness programs to "baby boomers" will miss this. General awareness programs to "baby boomers" will miss this. Outreach in HCV is similar to advertising a consumer product like soap, the markets are highly segmented & you must tailor "advertising"/outreach based on these segmented populations you are trying to reach.

How Many/Who HAS HCV in USA - (01/14/14) ....

[HCV Heterogeneity among various Latino groups] Prevalence of Hepatitis C Virus Infection in US Hispanic/Latino Adults: Results from the NHANES 2007-2010 and HCHS/SOL Studies - (01/15/14)

New NHANES: The Changing Epidemiology of Hepatitis C Virus Infection in the United States: National Health and Nutrition Examination Survey 2001 through 2010 - (01/13/14)

Source

5 things to know about acetaminophen

By Jacque Wilson, CNN
updated 11:58 AM EST, Thu January 16, 2014

(CNN) -- The Food and Drug Administration recently issued a warning to doctors about prescribing medications with more than 325 milligrams of acetaminophen. Although acetaminophen is harmless in small doses, it can cause liver damage if taken incorrectly.

Here are five things you should know about this popular painkiller:

1. It's not great for muscle pain.

Acetaminophen is part of a class of painkillers called non-opioid analgesics, which are used to treat mild or moderate pain. These include acetaminophen, ibuprofen and aspirin.

Non-opiod analgesics block an enzyme known as cyclooxygenase, or COX, according to Ewan McNicol, an assistant professor of anesthesiology at Tufts University. COX helps the body produce lipid compounds called prostaglandins that cause pain and inflammation when your cells are injured. Blocking this enzyme, therefore, helps prevent prostaglandins from causing you pain.

Most non-opiod analgesics work in the peripheral nervous system, or the nerves not included in your brain and spinal cord. But scientists believe acetaminophen works primarily in the central nervous system, attacking a slightly different form of the enzyme called COX-3.

"What this means to you is that acetaminophen is great for headaches, fever and minor aches and pains but won't reduce inflammation due to, say, a muscle sprain," McNicol explained.

2. It's found in more than Tylenol.

Though many people know that acetaminophen in the active ingredient in Tylenol, it's also found in many other over-the-counter drugs including (but not limited to) some Excedrin, Robitussin and Sudafed products.

Acetaminophen is also used in combination with opioids in prescription pain medications such as Percocet, Vicodin and Tylenol with codeine.

To find out whether your medications contain acetaminophen, read the drug label or the list of ingredients in the patient information leaflet that came with your prescription. Look for the word "acetaminophen" or the letters "APAP," an abbreviation sometimes used for the drug.

If you are still unsure, contact your doctor or pharmacist.

3. It's easy to accidentally take too much.

The FDA has set the recommended daily maximum for adults at 4,000 milligrams. It's easier to reach this limit than you might think; one gel tablet of Extra Strength Tylenol, for example, contains 500 mg.

Taking too much acetaminophen can lead to liver failure or death. Overdoses of the popular painkiller are some of the most common poisonings worldwide, according to the National Institutes of Health.

In April 2009, the FDA introduced new labeling requirements for drug manufacturers. Any product that contains acetaminophen must prominently identify the active ingredient on its display panel and must warn consumers about the potential for liver toxicity.

Consumers should not take more than the prescribed dose of any medication that contains acetaminophen, according to the FDA, and should avoid taking more than one acetaminophen product at a time.

4. It's not the best way to fight a hangover.

Most of us have popped a couple of painkillers after a night out to ward off a hangover. But experts say you should choose carefully when opening the medicine cabinet, especially if you're a chronic heavy drinker.

Taking acetaminophen with alcohol, even in small amounts, can increase your risk of liver damage and/or kidney disease.

Acetaminophen is primarily metabolized in the liver, where it is turned into nontoxic compounds that are eliminated through urination. But the liver needs something called glutathione to do that. If your glutathione levels are low -- which can be caused by chronic drinking, an unhealthy diet or fasting -- the drug may be metabolized into a more toxic substance, according to the National Institutes of Health.

Liver damage may occur after taking as few as four or five extra-strength pills over the course of the day, one NIH publication on alcohol and metabolism says. And another study showed that taking the recommended dose of acetaminophen with a small to moderate amount of alcohol can increase your risk of kidney disease by 123%.

You may not notice the signs of liver damage right away, the FDA says; some symptoms like loss of appetite and nausea can be mistaken for the flu (or that hangover). If you suspect you're at risk, contact your doctor immediately.

5. It's not like "a spoonful of sugar."

Children can take acetaminophen to fight pain or a fever, but parents should read drug labels carefully to avoid dosage errors.

The "directions" section of the label tells you whether the medicine is right for your child and how much to give, the NIH's website says(PDF). "If a dose for your child's weight or age is not listed on the label or you can't tell how much to give, ask your pharmacist or doctor what to do."

Liquid acetaminophen for infants and children is now sold in the same concentration: 160 mg/5 mL. That means infants need less; acetaminophen products for infants are usually packaged with an oral syringe instead of a dropper.

Parents should always use the measuring tool that comes with the medication, the FDA says -- never a kitchen spoon.

If your child takes too much acetaminophen, seek medical attention right away. You can also call the 24-hour Poison Control Center at 800-222-1222.

Source

Also See: Acetaminophen Prescription Combination Drug Products with more than 325 mg: FDA Statement - Recommendation to Discontinue Prescribing and Dispensing - FDA Release

Interferon-Free Combo of ABT-450, Ritonavir Helpful for Hep C

January 16, 2014

Interferon-Free Combo of ABT-450, Ritonavir Helpful for Hep C

(HealthDay News) – Treatment with an interferon-free combination of the protease inhibitor ABT-450 with ritonavir, or daclatasvir plus sofosbuvir, is associated with high rates of sustained virologic response in hepatitis C virus (HCV) infection, according to two studies published in the Jan. 16 issue of the New England Journal of Medicine.

Kris V. Kowdley, MD, from Mason Medical Center in Seattle, and colleagues conducted a phase 2b open-label study to evaluate multiple regimens of antiviral agents and ribavirin in 571 patients with HCV genotype 1 who had not received or not responded to treatment previously. The researchers found that for previously untreated patients who received three direct-acting antiviral agents (including ABT-450 with ritonavir) plus ribavirin, the sustained virologic response at 24 weeks was 88% with eight weeks of therapy and 95% for 12 weeks of therapy.

Mark S. Sulkowski, MD, from Johns Hopkins University in Baltimore, and colleagues conducted an open-label study involving 211 patients with HCV genotype 1 (previously untreated or with previous virologic failure with telaprevir or boceprevir), 2, or 3 infection who were randomized to receive daclatasvir plus sofosbuvir with or without ribavirin. The researchers found that 98% of patients with genotype 1 infection had a sustained virologic response at week 12 after therapy. Sustained virologic response at week 12 was 92% for genotype 2 and 89% for genotype 3. In addition, high rates of sustained virologic response at week 12 were seen among patients who received ribavirin and those who did not (94% and 98%, respectively).

"Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3," Sulkowski and colleagues write.

The Kowdley study was funded by AbbVie. The Sulkowski study was funded by Bristol-Myers Squibb and Pharmasset (Gilead).

Full Text - Kowdley (subscription or payment may be required)
Full Text - Sulkowski (subscription or payment may be required)

Source

Also See:

•  New Drug Combo Cures Toughest Cases of Hepatitis C, Hints to Future Injection-free Therapies
•  Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1

First regional study on hepatitis C and HIV co-infection launched in Asia

Source: Thomson Reuters Foundation - Thu, 16 Jan 2014 11:10 AM

Author: Thin Lei Win

A terminally ill man receives treatment at a hospice for those dying of AIDS, at Wat Prabat Nampu Buddhist temple in Lopburi on World AIDS day December 1, 2011. REUTERS/Sukree Sukplang

BANGKOK (Thomson Reuters Foundation) – The Foundation for AIDS Research (amfAR) has launched the first regional study in Asia looking at obstacles in treating people living with hepatitis C and HIV in low and middle-income countries.

Greater access to the antiretroviral therapy (ARV) has helped give HIV-positive people longer and better lives, but chronic health problems such as hepatitis C and tuberculosis are causing premature and unnecessary deaths, experts say.

Hepatitis C - which is prohibitively expensive to treat - can be cured but is often undiagnosed. Left untreated, the virus can lead to deadly liver disease.

An estimated 5 million people living with HIV worldwide - about 15 percent of all who are HIV-positive - are also infected with hepatitis C, of which a fifth are in Asia, according to amfAR.

“Our concern is that we can invest all our resources we have in treating somebody with HIV and give them the optimal antiretroviral therapy that we have access to, but they can still die of liver failure,” amfAR’s vice president Annette Sohn said Thursday.

“We know how to treat these infections, we just need the tools and distribute the knowledge to make that happen,” said Sohn, who is also director of amfAR’s Therapeutics Research, Education, and AIDS Training in Asia (TREAT Asia).

A course of hepatitis C therapy costs between $10,000 and $20,000, and could last up to 48 weeks.

The high cost for treatment, side effects including severe flu-like symptoms and a lack of experience in care for co-infected patients mean many in Asia go untreated, Sohn said.

In December, U.S. regulators approved a pill with fewer side effects, but it costs $1,000 a day and requires 12 weeks of treatment.

“We don’t see those drugs becoming immediately accessible in the low- and middle-income countries in the near future,” she said. “There are people who are dying of liver failure. We don’t feel like we can afford to wait.”

DRUG USE AND CO-INFECTION

The study, launched on Jan. 6 and expected to last a few years, will be implemented in four HIV treatment centres in the capitals of Indonesia, Thailand, Vietnam and Malaysia.

A total of 200 HIV-positive patients with hepatitis C or signs of liver disease will be offered free hepatitis C treatment integrated within routine HIV care. They will also receive support and education on treatment.

“What we’re hoping is through this project we learn as much as we can about what to do and what not to do in order to implement this sort of a programme on a broader scale,” Sohn said.

Experts say a large number of patients co-infected with HIV and hepatitis C are current or former injecting drug users.

A 2010 report by the Thai AIDS Treatment Action Group (TTAG) said about 90 percent of the roughly 30,000 to 60,000 injecting drug users in Thailand who are HIV positive also carry the hepatitis C virus.

In an interview with Thomson Reuters Foundation, TTAG said Thailand's failure to treat hepatitis C in HIV-positive injecting drug users means the HIV remains highly infectious in this group and is more likely to spread to other people.

This is one thing the amfAR study hopes to prevent.

“One of the main reasons why these countries were selected was because they have concentrated epidemics within populations of people who inject drugs or who have injected drugs in the past,” said Sohn, who added that HIV and hepatitis C co-infections have not received much attention in part because of stigma and discrimination.

“We cannot possibly control our HIV epidemic and hepatitis C epidemic… unless we ensure that people who inject drugs, whether currently or in the past, are included in these interventions and research studies.”

Source

Also See: amfAR Launches Hep C Study in Asia

Monitoring Inactive Hepatitis B Patients Is Cost-Effective Strategy

Provided by Science Daily

Jan. 15, 2014 — A novel study determined that monitoring inactive chronic hepatitis B (HBV) carriers is a cost-effective strategy for China. However, results published in Hepatology, a journal of the American Association for the Study of Liver Diseases, show that increasing treatment, monitoring and adherence to therapy are necessary to achieve significant health benefits at the population level.

The World Health Organization (WHO) estimates that roughly 2 billion individuals worldwide have been infected with HBV -- a virus causing acute or chronic liver disease that may lead to cirrhosis or liver cancer (hepatocellular carcinoma, HCC). WHO reports that 240 million are living with chronic HBV, with 1.4 million of those individuals in the U.S. according to estimates from the Centers for Disease Control and Prevention (CDC).

Previous research shows that 60% of the population in China has been infected with HBV and up to 10% are chronically infected, placing them at risk for life-threatening liver disease. In fact, medical evidence estimates that 500,000 Chinese die each year from HBV-related causes.

"China has the largest concentration of people infected with chronic HBV and understanding the health and economic impact is extremely important," explains Dr. Mehlika Toy from the Asian Liver Center at Stanford University School of Medicine who spearheaded the study while she was a Takemi Fellow at the Harvard School of Public Health in Boston, Massachusetts. "Our study is the first to analyze cost and cost-effectiveness of monitoring inactive CHB patients in Shanghai."

Using simulation models, the research team compared the current strategy of not monitoring inactive chronic HBV patients to a monitor and treat (M&T) strategy. The M&T strategy would include twice-yearly assessment of HBV and alanine transaminase (ALT) levels in patients with chronic HBV. For active HBV cases the researchers suggest treatment with entecavir, which evidence shows to be a cost-effective antiviral therapy in China.

Results show that there were 1.5 million adult carriers of HBV in Shanghai, with 63% of those hepatitis B virus e antigen (HBeAg) positive. The number of active cases of chronic HBV, were 258,139 HBeAg-positive group and 152,384 in the HBeAg-negative group. Researchers estimated that the M&T strategy would cost $20,730 (U.S.) and result in 15.45 quality-adjusted life-years (QALYs) per patient, compared to $20,455 and 15.35 QALYs for the current practice.

"Our findings suggest that monitoring of chronic HBV patients is cost-effective, but relies on identifying more cases of HBV infection, and increasing treatment, monitoring, and antiviral adherence to achieve health gains," concludes Dr. Toy. "We estimate that with adherence to monitoring and treatment, HCC could be reduced by 70% and mortality caused by chronic HBV by 83%."

Story Source:

The above story is based on materials provided by Wiley.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

1. Mehlika Toy, Joshua A Salomon, Jiang Hao, Gui Honglian, Hui Wang, Jiangshe Wang, Jan Hendrik Richardus, Qing Xie.Population health impact and cost-effectiveness of monitoring inactive chronic hepatitis B and treating eligible patients in Shanghai, China. Hepatology, 2013; DOI: 10.1002/hep.26934

Source

The impact of chronic hepatitis C infection on the circadian clock and sleep

Journal of Hepatology

Article in Press

Daniel Shouval

Received 8 January 2014; accepted 8 January 2014. published online 15 January 2014.
Accepted Manuscript

Please cite this article as: Shouval, D., The impact of chronic hepatitis C infection on the circadian clock and sleep, Journal of Hepatology (2014), doi: http://dx.doi.org/10.1016/j.jhep.2014.01.004

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

FOCUS,  April 2014

The impact of chronic hepatitis C infection on the circadian clock and sleep

Daniel Shouval

Liver Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel

Sleep disturbance with reversal of the day and night cycle is a well known phenomenon in patients with hepatic encephalopathy irrespective of etiology as shown in animal models and in humans1-3 . Indeed, insomnia, fatigue, depression and cognitive impairment are common symptoms in patients with chronic liver disease (CLD) with cirrhosis. During the past 15 years, several studies have been published on the impact of cirrhosis such as primary biliary cirrhosis, non-alcoholic fatty liver disease and Wilson's disease on the quality of sleep 4-6. However, it is less known that abnormal sleep patterns have also been documented in up to~ 50% of patients with cirrhosis in the absence of overt hepatic encephalopathy or even in patients with CLD without cirrhosis5 . It is however sometimes difficult to differentiate between an organic cause of fatigue and insomnia from psychiatric disorders of variable severity in CLD in general and in chronic hepatitis C patients in particular 7 . Sleep patterns are dictated by 24 hour circadian clocks, subjected to light and darkness cycles, which control numerous metabolic activities such as body temperature, blood pressure, melatonin, cortisol and growth hormone levels, urine output as well as mood and cognitive abilities. Such endogenous circadian cycles exist not only in humans but also in animals, plants, algae, bacteria and fungi8 . Disruption of clock genes which control the circadian rhythms have recently been linked to sleep disorders and have an impact on metabolic activities9,10. Sleep and circadian rhythms disruption may have serious consequences on emotional, cognitive and somatic responses. For example, inadequate sleep may lead to exhaustion, increased irritability, mood fluctuation such as depression, anxiety or anger, reduced concentration, attention deficit disorder, decreased memory, decreased productivity and creativity, drowsiness, unintended sleep, weight gain, metabolic abnormalities such as hyperglycemia and more11. (The interested reader is referred to a recent review entitled "Sleep Disorders in Chronic Liver Disease"3 ).

In the past two decades, referral of patients with chronic hepatitis C (CHC) is dominating the practice of clinical hepatologist worldwide, yet sleep disturbances in CHC patients without cirrhosis have received relatively little attention3,12,13 . In the present issue of the journal, Dr Heeren and co-workers from the Hannover Medical School in Germany report their observations on altered sleep quality in a cohort of CHC patients without overt cirrhosis or classical hepatic encephalopathy14. The study cohort (N=20, mean age 56.8y) was recruited from a small subgroup (N=143) of the original HCV infected 1833 women who received an HCV contaminated anti-D immunoglobulin over three decades ago 15. Thus twenty anti-HCV positive, genotype 1b patients of whom 12 were still HCV-RNA positive by PCR participated in the study. The control population consisted of 19 age matched healthy females (mean age 55.3y). The unique characteristic relevant to the goals of the discussed study is the relatively benign course of CHC without cirrhosis over a period of more than thirty years in this selected group of women who nevertheless complained among other symptoms of weakness, fatigue and decreased exertional capacity

The methodology used to assess the various study variables is broad and quite complex. Participants were asked to fill a number of questionnaires including the Pittsburgh Sleep Quality Index measuring sleep quality; the Epworth Sleepiness Scale measuring daytime sleepiness; the Fatigue Impact Scale measuring the impact of fatigue on daily activity; the Back Depression Inventory measuring depression; the Hospital Anxiety and Depression Scale measuring emotional alteration and the SF-36 questionnaire measuring health related quality of life. Furthermore, patients had to fill a sleep diary and use an actigraph which is a wrist worn device for monitoring of motor activity over a period of 24 hours/day for 5 days. Obtained scores from the various questionnairs filled by the study and control groups as well as actigraphy scores were compared and a Spearman correlation test was used to evaluate a relationship between fatigue, quality of life, sleep parameters and actigraphy results.

The major findings of this study indicate that in contrast to healthy controls, patients with a history of chronic hepatitis C virus infection without overt cirrhosis may develop a disrupted circadian rhythm. This so called circadian arrhythmia is associated with an altered sleep pattern, insomnia , fatigue, depression and reduced quality of life which correlate with one another. Although patients displayed an increased nocturnal activity, no correlation could be established between fatigue and sleep pattern abnormality and 24 hour activity level.

Comments: The reported results suggest and confirm previous observations that sleep disruption and its consequences should be regarded as an extra hepatic manifestation of chronic hepatitis C . Furthermore, these symptoms may already be present in patients with mild chronic hepatitis C without clinical evidence for cirrhosis. A previous report found a strong association between reduced survival and sleep disorders in patients with advanced liver disease16. The present cohort of patients with relatively mild CHC is already followed for more than 3 decades and so far there is apparently no indication to suspect a worse prognosis despite the reported abnormal sleep pattern. Interestingly, the abnormal sleep pattern was present in both the 12 viremic patients as well as in those 7 patients who were HCVRNA negative by PCR. In this context it is worthwhile to mention a recent report suggesting that primary and precursor forms of liver specific microRNA (miR122) are regulated in a circadian rhythm in the liver of animals17. In the detailed and well referenced discussion of this paper, the authors express their belief that based on previous functional imaging studies, the described symptoms in both HCV-RNA positive and negative patients are the result of an encephalopathy which is independent of the state of viremia. However, the relatively small sample size and the absence of functional imaging data for the specific study cohort does not enable yet a firm conclusion regarding the role of viremia in the above described symptoms.

Heeren and co-workers' report is the result of an extensive effort which is a case control study and descriptive by nature. The investigators utilized a wide range of methods to reach their conclusions but their results do not provide a clue regarding the mechanism(s) involved in the sleep disturbance and its consequences in CHC and this will remain a goal of future research. Aberrant sleep patterns have previously been linked to central nervous system involvement in persistent HCV infection affecting up to 65% of CHC patients12,13,18. It has been suggested that sleep and the circadian system regulate a number of immune functions or vice versa19,20. For example, the number of undifferentiated naïve T cells and production of proinflammatory cytokines peak during early nocturnal sleep while cytotoxic NK cells and anti-inflammatory cytokines peak during day time19. The impact of past or present HCV infection on these parameters in the context of sleep disturbances is still unknown. Sleep and the circadian timing systems are driven by a complex interaction between multiple brain regions, neurotransmitters and hormones. Moreover, up to 20 clock genes and their protein products have been linked to control of circadian rhythms through translational-transcriptional feedback loops 8,11. However the interaction of the hepatitis C virus with these genes and its impact on the molecular clock is still unexplored except for a recent observation in vitro that a circadian protein called PER2 interferes in viral replication21.

In summary, the discussed report provides descriptive evidence that a history of past or present mild chronic hepatitis C virus infection even without clinical evidence for cirrhosis or "traditional" hepatic encephalopathy is associated with an altered sleep pattern which has a negative impact on quality of life and well being.

References

1 Jimenez-Anguiano, A. et al. Modification of sleep architecture in an animal model of experimental cirrhosis. World J Gastroenterol 15, 5176-5180 (2009.(

2 Zee, P. C., Mehta, R., Turek, F. W. & Blei, A. T. Portacaval anastomosis disrupts circadian locomotor activity and pineal melatonin rhythms in rats. Brain Res 560, 17- 22, doi:0006-8993(91)91209-J [pii] (1991.(

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A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4

Journal of Hepatology

Article in Press

Bradley Vince,John M. Hill,Eric J. Lawitz,William O’Riordan,Lynn R. Webster,Daniel M. Gruener,Ricky S. Mofsen,Abel Murillo,Eileen Donovan, Jie Chen,Joseph F. McCarville,John Z. Sullivan-Bólyai,Douglas Mayers,Xiao-Jian Zhou

Received 8 October 2013; received in revised form 29 December 2013; accepted 6 January 2014. published online 15 January 2014.

Abstract

Background & Aims

Samatasvir is a pan-genotypic inhibitor of the hepatitis C (HCV) nonstructural protein 5A (NS5A). This study evaluated the antiviral activity, pharmacokinetics and safety of samatasvir monotherapy in treatment-naïve subjects infected with HCV genotype 1-4.

Methods

Thirty-four genotype 1 and thirty genotype 2, 3 or 4 subjects were randomized to receive for 3 days placebo or samatasvir 25-100 mg per day. Plasma samples for HCV RNA, pharmacokinetics and sequencing were collected up to day 10.

Results

Samatasvir achieved potent antiviral activity across genotypes: mean maximum reductions from baseline were 3.2-3.6 (genotype 1a), 3.0-4.3 (genotype 1b), 3.2-3.4 (genotype 3) and 3.6-3.9 (genotype 4) log₁₀/mL respectively; no viral rebound was observed during the 3-day treatment period. For genotype 2 HCV, samatasvir was active in subjects with NS5A L31 polymorphism at baseline (individual range 2.5-4.1 log₁₀/mL), but showed minimal activity in those with baseline M31 polymorphism. Samatasvir exhibited a long plasma half-life of approximately 20 hours which supports once daily dosing. Samatasvir was well tolerated in all subjects with no safety-related discontinuations or serious adverse events. The most common adverse events included constipation, nausea and headache and occurred at similar frequency in active and placebo subjects. All events were mild or moderate in intensity. There were no patterns or dose dependence of adverse events, vital signs, laboratory parameters or electrocardiograms.

Conclusions

Samatasvir 25-100 mg monotherapy for 3 days was well tolerated and induced a rapid and profound reduction in plasma HCV RNA in subjects infected with HCV genotype 1-4. Samatasvir is being evaluated in combination with other direct-acting antiviral agents in subjects with HCV infection.

Abbreviations: HCV, hepatitis C virus, NS5A, nonstructural protein 5A, DAA, direct-acting antiviral agent, EC₅₀, 50% effective concentration, CYP, cytochrome P450, HBV, hepatitis B virus, HIV, human immunodeficiency virus, QD, once daily, BID, twice daily, AE,adverse event, BMI, body mass index, HCC, hepatocellular carcinoma, ECG, electrocardiogram, SAE, serious adverse event, PK,pharmacokinetic(s), AM, morning, PM, evening, C_max, maximum concentration, T_max, time to C_max, C_τ, predose trough concentration, AUC,area under curve, t_1/2, half-life, EC₉₀, 90% effective concentration

Keywords: Samatasvir, NS5A inhibitor, Hepatitis C virus, Pan-genotypic anti-HCV activity, IDX719, NS5A, Chronic hepatitis C, Pan-genotypic antiviral activity, Direct-acting antiviral agents, Pharmacokinetics

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Bristol-Myers Squibb Co.'s Daclatasvir May Prove a Winner

Provided by The Motley Fool

By Todd Campbell | More Articles
January 15, 2014 | Comments (0)

A seemingly late start had most thinking Bristol-Myers Squibb's (NYSE: BMY ) hepatitis C drug daclatasvir would prove an also-ran in the race for market share.

But a savvy move to focus overseas and seemingly eye-popping results for the drug when combined with Gilead's  (NASDAQ: GILD ) Sovaldi are starting to make it look as if daclatasvir has a better chance to capture sales than competitors Johnson & Johnson(NYSE: JNJ ) and AbbVie (NYSE: ABBV ) .

New therapies entering the growing market
Two of the highest-profile companies in the hunt for these therapies have been Gilead, which acquired Sovaldi in an $11 billion deal back in 2010, and Johnson, which has been nipping at Sovaldi's heels with its Olysio.

Both drugs won FDA approval heading into year's end, suggesting a very interesting first quarter for industry watchers. However, Gilead is likely to have the advantage, given, as I previously highlighted, that Sovaldi was more effective in a big subset of the hepatitis C population. That suggests Olysio may struggle to carve out a niche of its own.

But despite the early lead in approval for Gilead and Johnson, Bristol appears unfazed. In a prescient decision to focus on Japan at a time when the country is becoming friendlier to drugmakers, Bristol appears to have an edge in treating Japan's 1 million hepatitis C patients.

Impressive phase 2 study results showing that a combination of daclatasvir with Gilead's Sovaldi cleared the disease in 100% of patients makes Bristol's potential even more intriguing, especially since all those patients had previously failed on prior-generation therapies Invicek and Victrelis.

While Gilead chose to opt out of moving the drug combo into phase 3 trials, doctors, patients, and regulators have been less willing to give up on it. As a result, European regulators approved a compassionate-use program for the combination last fall for use in the most critical cases.

That use could expand if the EU approves commercialization of daclatasvir this year. If it does, then it's certainly possible the FDA will follow suit.

An approval and groundswell in demand would then put the pressure on payers, who might otherwise balk at paying for both drugs, which could run well north of $100,000 given Sovaldi's $84,000 cost per course of treatment.

More developments are coming
Gilead's reluctance to move ahead with Bristol probably stems from the success it's having with its own oral program. The company has reported strong data supporting its Sovaldi-plus-ledipasvir combination, showing that it cleared the disease in 95% of genotype 1 patients. Gilead plans to file with the FDA for approval of that therapy in the first quarter.

AbbVie is also vying for FDA approval with its own three-drug oral cocktail. The combination of AbbVie compounds cleared the disease in 96% historically tough-to-treat genotype 1a patients over 12 weeks of treatment in phase 3 trials. 

Fool-worthy final thoughts
The global need for hepatitis C therapies is big and growing. More than 170 million are infected worldwide, according to the World Health Organization. And 20,000 to 30,000 more are likely to be diagnosed with the disease each year in the United States. That has drug wholesaler Express Scripts calling for a quadrupling of spending in the U.S. on hepatitis C over the next three years, making the disease the fastest-growing indication for specialty drugs.

As a result, Bristol is looking at other ways to maximize daclatasvir's appeal, including pairing the drug up with Vertex Pharmaceuticals' (NASDAQ: VRTX )  VX-135. Vertex, the company behind former blockbuster hepatitis C treatment Incivek, recently reported that combining VX-135 with daclatasvir cleared the disease in 83% of patients over just four weeks. If those results continue in phase 3, daclatasvir may have an opportunity to win additional market share as doctors look for shorter treatment periods.

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Todd Campbell has no position in any stocks mentioned. Todd owns E.B. Capital Markets, LLC. E.B. Capital's clients may or may not have positions in the companies mentioned. Todd also owns Gundalow Advisors, LLC. Gundalow's clients do not have positions in the companies mentioned. The Motley Fool recommends Gilead Sciences, Johnson & Johnson, and Vertex Pharmaceuticals and also owns shares of Johnson & Johnson. Try any of our Foolish newsletter services free for 30 days. We Fools don't all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

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SVR12 is higher than SVR24 in treatment-naïve hepatitis C genotype 1 patients treated with peginterferon plus ribavirin

Authors: Thorlund K, Druyts E, Mills EJ

Published Date January 2014 Volume 2014:6 Pages 49 - 58

DOI: http://dx.doi.org/10.2147/CLEP.S53302

Received: 20 August 2013
Accepted: 10 October 2013
Published: 15 January 2014

Kristian Thorlund,^1,2 Eric Druyts,^3,4 Edward J Mills^1,4
1Stanford Prevention Research Center, Stanford University, Stanford, CA, USA;²Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada; ³School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada; ⁴Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada

Background: Randomized clinical trials (RCTs) of interventions for the hepatitis C virus have historically used sustained virological response (SVR) at 24 weeks after treatment (SVR24) as the key effect measure. However, recent RCTs investigating the efficacy of new direct acting agents (DAAs) have used SVR at 12 weeks after treatment (SVR12). While there is evidence to suggest SVR24 and SVR12 are similar in patients receiving new DAAs, this is unlikely to be true for patients receiving backbone peginterferon-ribavirin control treatment. Establishing the difference between SVR12 and SVR24 for patients receiving peginterferon-ribavirin treatment is therefore necessary to avoid biased interpretations of the benefits of newer DAAs.

Methods: We searched the MEDLINE^®, Embase™, and Cochrane CENTRAL for RCTs with a peginterferon-ribavirin arm that used SVR24 and/or SVR12. As no RCTs reported on both, we pooled SVR12 and SVR24 proportions using conventional meta-analysis. Proportions were pooled separately for peginterferon alpha-2a and alpha-2b. Further, a Bayesian meta-regression model was employed to estimate the difference between SVR12 and SVR24.

Results: Thirty-five RCTs including a peginterferon arm were identified. Twenty-four trials included a peginterferon alpha-2a plus ribavirin arms, of which 20 reported SVR24 and five reported SVR12. Seventeen trials included a peginterferon alpha-2b plus ribavirin arm, of which 16 reported SVR24 and one reported SVR12. Using Bayesian meta-regression, the pooled SVR12 was 6% higher than SVR24 with peginterferon alpha-2a (53% versus 47%) and 5% higher with peginterferon alpha-2b (45% versus 40%) and 95% credible intervals (CrIs) were only marginally overlapping. The meta-regression also demonstrated a marginally significant relative risk of 1.13 (95% CrI 0.99–1.26) of SVR12 versus SVR24. The conventional pairwise meta-analyses were consistent with these findings.

Conclusion: Considering the relatively large difference observed between SVR12 and SVR24, it seems reasonable to insist that future clinical trials report both to allow for complete transparency and clarity in their interpretation.

Keywords: sustained virological response, meta-regression, direct acting antivirals

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Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1

ORIGINAL ARTICLE

Kris V. Kowdley, M.D., Eric Lawitz, M.D., Fred Poordad, M.D., Daniel E. Cohen, M.D., David R. Nelson, M.D., Stefan Zeuzem, M.D., Gregory T. Everson, M.D., Paul Kwo, M.D., Graham R. Foster, F.C.R.P., Mark S. Sulkowski, M.D., Wangang Xie, Ph.D., Tami Pilot-Matias, Ph.D., George Liossis, B.A., Lois Larsen, Ph.D., Amit Khatri, Ph.D., Thomas Podsadecki, M.D., and Barry Bernstein, M.D.

N Engl J Med 2014; 370:222-232 January 16, 2014 DOI: 10.1056/NEJMoa1306227

BACKGROUND

An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin.

METHODS

In this phase 2b, open-label study with 14 treatment subgroups, 571 patients without cirrhosis who had not received treatment previously or who had not had a response to prior therapy were randomly assigned to a regimen of ABT-450/r, combined with ABT-267 or ABT-333 or both, for 8, 12, or 24 weeks and received at least one dose of therapy. All the subgroups but 1 also received ribavirin (dose determined according to body weight). The primary end point was sustained virologic response at 24 weeks after the end of treatment. The primary efficacy analysis compared rates between previously untreated patients who received three direct-acting antiviral agents and ribavirin for 8 weeks and those who received the same therapy for 12 weeks.

RESULTS

Among previously untreated patients who received three direct-acting antiviral agents (with the ABT-450/r dose administered as 150 mg of ABT-450 and 100 mg of ritonavir) plus ribavirin, the rate of sustained virologic response at 24 weeks after treatment was 88% among those who received the therapy for 8 weeks and 95% among those who received the therapy for 12 weeks (difference, −7 percentage points; 95% confidence interval, −19 to 5; P=0.24). The rates of sustained virologic response across all treatment subgroups ranged from 83 to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia. Eight patients (1%) discontinued treatment owing to adverse events.

CONCLUSIONS

In this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. (Funded by AbbVie; ClinicalTrials.gov number, NCT01464827.)

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HCV Therapy: High Rate of Viral Clearance, No Injections

Medscape Medical News

Jennifer Garcia
January 15, 2014

Two phase 2, open-label studies evaluating the safety and efficacy of all-oral combination therapies for patients infected with hepatitis C virus (HCV) have shown that high rates of sustained virologic response (SVR) are possible even in the absence of interferon. Results from both studies were published in the January 16 issue of the New England Journal of Medicine.

Patients enrolled in both studies were between 18 and 70 years of age with no evidence of cirrhosis.

In the first study, Mark S. Sulkowski, MD, from Johns Hopkins University, Baltimore, Maryland, and colleagues evaluated the efficacy of combination therapy with once-daily, oral antiviral drugs daclatasvir (60 mg daily) and sofosbuvir (400 mg daily) for patients infected with HCV genotypes 1, 2, or 3. Patients were treated for 24 weeks, and use of ribavirin as part of the treatment protocol was optional.

The US Food and Drug Administration recently approved sofosbuvir for the treatment of HCV in combination with ribavirin or ribavirin and interferon, depending on the HCV genotype being treated. Daclatasvir remains an investigational agent.

Overall, 211 patients enrolled in the study. Among those with genotype 1 infection, 126 were previously untreated and 41 had failed previous therapy with telaprevir or boceprevir plus peginterferon alfa-ribavirin.

Among patients with HCV genotype 1, researchers found that 164 (98%) previously untreated patients and 40 (98%) patients who had failed traditional therapy demonstrated a SVR (HCV RNA < 25 IU/mL) at week 12 after the end of therapy. High rates of SVR were also noted at week 12 among patients with HCV genotype 2 (92% of 26 patients) and those with HCV genotype 3 (89% of 18 patients).

"Our study shows that the combination of an NS5A inhibitor and an NS5B inhibitor was associated with high cure rates in a range of HCV-infected patients, including patients who had persistent HCV variants conferring resistance to protease inhibitors after unsuccessful treatment with telaprevir or boceprevir," write Dr. Sulkowski and colleagues.

The authors note that response rates were similar between patient groups treated with or without ribavirin; however, patients treated with ribavirin demonstrated a greater decrease in hemoglobin.

The second study evaluated an 8-, 12-, and 24-week all-oral, interferon-free treatment regimen among 571 patients with HCV genotype 1 who were previously untreated or who had failed prior therapy. The study, led by Kris V. Kowdley, MD, from the Virginia Mason Medical Center, Seattle, Washington, evaluated various dosage combinations of the NS3/4A protease inhibitor ABT-450 with ritonavir (ABT-450/r), combined with nonnucleoside NS5B polymerase inhibitor ABT-267, ABT-333, or both. All but 1 subgroup also received ribavirin.

The researchers found that SVR ranged from 83% to 100% across all treatment groups. The SVR at 24 weeks among previously untreated patients administered ABT-450/r plus ribavirin was 88% among those treated for 8 weeks and 95% among those treated for 12 weeks. Treatment beyond 12 weeks did not appear to confer any additional benefit.

HCV Therapy Without Injections

"The current standard of care for chronic HCV genotype 1 infection is pegylated interferon (peginterferon) and ribavirin, with a protease inhibitor (boceprevir or telaprevir)," write Dr. Kowdley and colleagues. The emergence of new oral antiviral therapies could mean the end of multipill and injectable drug regimens.

In an interview with Medscape Medical News, William Balistreri, MD, from the Cincinnati Children's Hospital Medical Center in Ohio, said: "[T]hese 2 preliminary studies are clearly promising, offering the hope for a 'cure' of chronic hepatitis C with a less complex, shorter-duration, interferon-free, all-oral regimen."

A similarity between the studies was the finding that both treatment-naive patients and those who had failed previous therapy demonstrated high rates of SVR with these oral, interferon-free regimens. In previous studies, "only approximately one third of patients who had not had a response to prior therapy with peginterferon and ribavirin had a sustained virologic response when re-treated with the addition of a protease inhibitor," write Dr. Kowdley and colleagues. These findings provide hope that these newer regimens may be of benefit in difficult-to-treat patients with HCV.

Adverse effects were similar between the studies and included fatigue, headache, and nausea; they compare favorably with the rate of adverse effects previously documented with standard HCV therapy.

Although the results of both studies offer hope to patients infected with HCV, "[w]e await 'real-world' experience with these [agents], once full approval and widespread use occur. This will include reports of barriers encountered, including cost, efficacy, and adverse effects," concluded Dr. Balistreri.

Funding for Dr. Sulkowski's study was provided by Bristol-Myers Squibb and Pharmasset (Gilead). Funding for Dr. Kowdley's study was provided by AbbVie. Dr. Sulkowski is a paid consultant for Bristol-Myers Squibb and Gilead. Full conflict-of-interest information for all contributors is available on the journal's Web site. Dr. Balistreri has disclosed no relevant financial relationships.

New Engl J Med. 2014;370:211-221, 222-232. Sulkowski abstract, Kowdley abstract

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New Drug Combo Cures Toughest Cases of Hepatitis C, Hints to Future Injection-free Therapies

Published: January 15, 2014. By Johns Hopkins Medicine
http://www.hopkinsmedicine.org

Efforts to cure hepatitis C, the liver-damaging infectious disease that has for years killed more Americans than HIV/AIDS, are about to get simpler and more effective, according to new research at Johns Hopkins and elsewhere.

In a study to be reported in the Jan. 16 issue of the New England Journal of Medicine, researchers say combination treatments involving a pair of experimental, oral antiviral drugs, daclatasvir and sofosbuvir, were safe and highly effective in the treatment of hepatitis C. The combination therapy worked well even in the patients who are hardest to treat, in whom the conventional "triple therapy" with hepatitis C protease inhibitors, telaprevir or boceprevir, plus peginterferon and ribavirin had failed to cure the infection.

"This research paves the way for safe, tolerable and effective treatment options for the vast majority of those infected with hepatitis C," says study leader Mark Sulkowski, M.D., medical director of the Johns Hopkins Center for Viral Hepatitis. "Standard treatments for the disease are going to improve dramatically within the next year, leading to unprecedented advances for the treatment of patients infected with the hepatitis C virus."

The research was conducted on 211 men and women with any of the three major types of the disease who were treated at 18 medical centers across the United States and Puerto Rico. Among patients with genotype 1 — the most common strain of the infection in the United States — 98 percent of the 126 previously untreated patients and 98 percent of 41 patients whose infections remained even after the triple therapy were considered cured, with no detectable virus in their blood three months after the treatment had stopped. Results were similar in study participants infected with genotypes 2 or 3, strains which are less common in the United States.

The study participants took a daily combination of 60 milligrams of daclatasvir and 400 milligrams of sofosbuvir, with or without ribavirin.

On Dec. 6, the U.S. Food and Drug Administration (FDA) approved sofosbuvir in combination with peginterferon and ribavirin for the treatment of genotype 1 infection and in combination with only ribavirin for genotype 2 and 3 infection. Daclatasvir has not yet been approved by the FDA.

Sulkowski says that if declatasavir and other new drugs for hepatitis C win approval from the FDA, the dreaded weekly injections of peginterferon will be a thing of the past.

Sulkowski, a professor at the Johns Hopkins University School of Medicine, also says that the so-called "pill burden" of what had been standard therapy for genotype 1 could go down from some 18 pills per day and one injection per week to as few as one or two pills per day and no injections. Side effects from the new pill combination were generally mild, but included fatigue, headache and nausea, a safety profile that Sulkowski says compares favorably with that of the peginterferon-based therapy, which is tied to severe side effects which may include fatigue and depression.

The new study is one of the first to show that hepatitis C can be cured without the use of ribavirin, which is known to cause anemia.

The advent of simpler pill-only regimens, Sulkowski adds, should make it easier for those infected with hepatitis C to be cured, preventing the development of liver cancer and liver failure and obviating the need for liver transplant. Currently, he says, fewer than 5 percent of the estimated 3.2 million Americans with hepatitis C have been cured, according to the U.S. Centers for Disease Control and Prevention (CDC). Further, the CDC estimates that between 50 and 75 percent of people who live with chronic hepatitis C are unaware that they are infected.

Sulkowski says the arrival of simpler treatment regimens could not come soon enough. Many of the people diagnosed with the infection, mainly those born between 1945 and 1965, were infected during the 1970s and 1980s through injection drug use and tainted blood transfusions and are now suffering from cirrhosis and liver cancer tied to chronic infection. This is why, he says, the CDC recommended hepatitis C screenings in 2012 for all baby boomers.

Sulkowski says that further research is being performed by Gilead Sciences of Foster City, Calif., on a regimen that combines sofosbuvir with another experimental drug it manufactures, called ledipasvir, into a single tablet which can be taken once a day. Ledipasvir is similar to daclatasvir, which is made by Bristol-Myers Squibb of Princeton, N.J., in that it inhibits replication of the hepatitis nonstructural protein NS5A. The combination of sofosbuvir and ledipasvir has not yet been approved by the FDA.

The newly published study, which took two years to complete, was funded by Gilead Sciences and Bristol-Myers Squibb. Sulkowski is a paid consultant to both Gilead Sciences and Bristol-Myers Squibb. The terms of his arrangements are managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Besides Sulkowski, other study investigators involved in this study were Maribel Rodriguez-Torres, M.D., at the Fundacion de Investigacion in San Juan, Puerto Rico; K. Rajender Reddy, M.D., at the University of Pennsylvania; Tarek Hassanein, M.D., at Southern California Liver Center in Coronado, Calif.; Ira Jacobson, M.D., at Weill Cornell Medical College in New York; Eric Lawitz, M.D., at the University of Texas Southwestern Medical Center in San Antonio; Anna Lok, M.D., at the University of Michigan, Ann Arbor; Federico Hinestrosa, M.D., at Orlando Immunology Center in Florida; Paul Tuluvath, M.D., at Mercy Medical Center in Baltimore, Md.; Howard Schwartz, M.D., at Miami Research Associates in Florida; David Nelson, M.D., at the University of Florida; and Gregory Everson, M.D., at the University of Colorado Denver.

Additional research support was provided by David Gardner, M.D.; Timothy Eley, Ph.D.; Megan Wind-Rotolo, Ph.D.; Shu-Pang Huang, Ph.D.; Min Gao, Ph.D.; Dennis Hernandez, Ph.D.; Fiona McPhee, Ph.D.; Diane Sherman, M.S.; Robert Hindes, M.D.; Claudio Pasquinelli, M.D., Ph.D.; and Dennis Grasela, Ph.D., all from Bristol-Myers Squibb; and by William Symonds, Pharm.D., from Gilead Sciences.

For additional information, go to:
http://www.hopkinsmedicine.org/Medicine/viralhep/patientcare/
http://content.nejm.org/

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