Tuesday, August 16, 2011

Hepatitis Digest;HCV abstract-BMS-790052, Liver Cancer,Vitamin D and Diabetes

HCV abstracts

Aug 2011;
Multiple ascending dose study of BMS-790052, an NS5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1

Nettles RE, Gao M, Bifano M, Chung E, Persson A, Marbury TC, Goldwater R, Demicco MP, Rodriguez-Torres M, Vutikullird A, Fuentes E, Lawitz E, Carlos Lopez-Talavera J, Grasela DM; Hepatology (Aug 2011)

The antiviral activity, resistance profile, pharmacokinetics (PK), safety and tolerability of BMS-790052, an NS5A replication complex inhibitor, were evaluated in a double-blind, placebo-controlled, sequential panel, multiple ascending dose study. Thirty patients with chronic hepatitis C virus (HCV) genotype 1 infection were randomized to receive a 14-day course of BMS-790052 (1, 10, 30, 60 or 100 mg once daily or 30 mg twice daily) or placebo in a ratio of 4:1.

RESULTS: The mean maximum decline from baseline in HCV RNA ranged from 2.8 to 4.1 log(10) IU/mL; the placebo group showed no evidence of antiviral activity. Most patients experienced viral rebound on or before day 7 of treatment with BMS-790052 monotherapy; viral rebound was associated with viral variants that had been previously implicated in resistance development in the in vitro replicon system. The PK profile was supportive of once-daily dosing with median peak plasma concentrations at 1-2 hours postdose and mean terminal half-life of 12-15 hours. Steady state was achieved following 3-4 days of daily dosing. BMS-790052 was well tolerated in all dose groups with adverse events occurring with a similar frequency in BMS-790052- and placebo-treated groups. There were no clinically relevant changes in vital signs, laboratory, or electrocardiogram parameters.

CONCLUSION: BMS-7590052 is the first NS5A replication complex inhibitor with multiple dose proof-of-concept in clinic. At doses of 1-100 mg daily, BMS-790052 was well-tolerated, had a PK profile supportive of once-daily dosing, and produced a rapid and substantial decrease in HCV-RNA levels in patients chronically infected with HCV genotype 1. (HEPATOLOGY 2011.)

Genotypic and phenotypic analysis of variants resistant to HCV NS5A replication complex inhibitor BMS-790052: In Vitro and In Vivo correlations
Fridell RA, Wang C, Sun JH, O' Boyle DR, Nower P, Valera L, Qiu D, Roberts S, Huang X, Kienzle B, Bifano M, Nettles RE, Gao M; Hepatology (Aug 2011)

The NS5A replication complex inhibitor BMS-790052 inhibits hepatitis C virus (HCV) replication with picomolar potency in preclinical assays. This potency translated in vivo to a substantial antiviral effect in a single-ascending dose study and a 14-day multiple-ascending dose (MAD) monotherapy study. However, HCV RNA remained detectable in genotype 1a-infected patients at the end of the MAD study. In contrast, viral breakthrough was observed less often in patients infected with genotype 1b and, in several patients, HCV RNA declined and remained below the level of quantitation (<25 IU/mL) through the duration of treatment. Here we report results of the genotypic and phenotypic analyses of resistant variants in 24 genotype 1-infected patients who received BMS-790052 (1, 10, 30, 60 and 100 mg, once daily or 30 mg, twice daily) in the 14-day MAD study. Sequence analysis was performed on viral cDNA isolated from serum specimens collected at baseline and days 1 (4, 8, and 12 hours), 2, 4, 7, and 14 postdosing. Analyses of the sequence variants (i) established a correlation between resistant variants emerging in vivo with BMS-790052 treatment and those observed in the in vitro replicon system (major substitutions at residues 28, 30, 31 and 93 for genotype 1a, and residues 31 and 93 for genotype 1b); (ii) determined the prevalence of variants at baseline and the emergence of resistance at different times during dosing; and (iii) revealed the resistance profile and replicative ability (fitness) of the variants.

CONCLUSION: Although resistance emerged during monotherapy with BMS-790052, the substantial anti-HCV effect of this compound makes it an excellent candidate for effective combination therapy. (HEPATOLOGY 2011.)

BMS-790052 Plus BMS-650032

From CCO;EASL 2011
Expert Analysis
BMS-790052 Plus BMS-650032 With or Without Peginterferon alfa-2a/Ribavirin in Previous Null Responders With Genotype 1 HCV Infection
AJ is a genotype 1 HCV–infected patient who experienced a null response with previous peginterferon/ribavirin therapy. He is hesitant to start treatment with telaprevir or boceprevir once approved, as he does not feel that that the chances of SVR are worth the adverse effects he experienced with peginterferon previously. He is curious to know whether any data thus far have shown SVR among patients treated with an interferon-free regimen.

How can you advise this patient?

To View Capsule Summary Free Registration Is Required

Stefan Zeuzem, MD: In another study investigating the efficacy of combining DAA agents, Lok and colleagues[35] combined the HCV NS5A replication complex inhibitor, BMS-790052, with the HCV NS3 protease inhibitor, BMS-650032, with or without peginterferon alfa-2a/ribavirin in patients infected with genotype 1 HCV who experienced previous null response to peginterferon/ribavirin therapy (Capsule Summary). In this open-label phase IIa trial, 21 patients were randomized to dual therapy with BMS-790052 60 mg once daily plus BMS-650032 600 mg twice daily or to quadruple therapy with the same doses of BMS-790052 and BMS-650032 plus peginterferon alfa-2a/ribavirin. Treatment was for 24 weeks, and patients with virologic breakthrough were eligible to add peginterferon/ribavirin therapy for up to 48 additional weeks. The primary endpoint was SVR12.

Although the patient numbers are small, all 10 patients receiving quadruple therapy for 24 weeks achieved SVR12. By contrast, only 4 out of 11 patients receiving dual therapy achieved SVR12. Patients were stratified by genotype 1 HCV subtype and no more than 2 patients with genotype 1b HCV were allowed in each treatment arm. The investigators did not state why there was a limit to the number of patients with genotype 1b HCV; however, in the dual therapy arm, both patients with genotype 1b infection achieved SVR12. The high SVR12 rate among patients with genotype 1b infection receiving dual therapy would be more convincing if there would have been more than 2 patients infected with this HCV subtype enrolled.

Graham R. Foster, FRCP, PhD: Virologic response differences according to genotype 1 subtype have been demonstrated in clinical studies with protease inhibitors as discussed previously, but there are few data as yet on the impact of HCV subtype on clinical response to NS5A inhibitors.
In an ascending dose study of another NS5A inhibitor, AZD7295, HCV RNA levels exhibited dose-dependent reductions among patients with genotype 1b HCV, but not among patients with genotype 1a or 3 infection.[36]

Stefan Zeuzem, MD: An analysis of in vitro culture systems demonstrated a lower EC50 of BMS-790052 for genotype 1b vs 1a; however, the values for both subtypes are in the subnanomolar range and the dose administered in this trial should have been effective for both subtypes.[37] Therefore, it remains an open question and further studies are needed.
In the current BMS-790052/BMS-650032 combination study, 6 out of 11 patients treated with dual therapy did not achieve undetectable HCV RNA at the end of therapy (Week 24) and experienced virologic breakthrough at various time points. A seventh patient experienced viral relapse, resulting in 4 patients (36%) with SVR12, including both patients with genotype 1b infection and 2 patients with genotype 1a infection. On the other hand, patients receiving quadruple therapy achieved an impressive 100% rate of undetectable HCV RNA at the end of treatment, and this outcome was maintained at 12 weeks after stopping therapy as mentioned previously.
At posttreatment Week 24, 1 patient in the quadruple therapy arm appeared to have detectable but not quantifiable HCV RNA; however, a retest 35 days later showed that the patient once again had undetectable HCV RNA. Therefore, the SVR rate at posttreatment Week 24 in this arm was formally 90%. The fact that all patients who received just 24 weeks of quadruple therapy were cured is a very impressive result considering that all of the patients enrolled in this trial experienced a previous null response, defined as a < 2 log10 IU/mL decline in HCV RNA after 12 weeks of peginterferon/ribavirin therapy.

Graham R. Foster, FRCP, PhD: This study represents an exciting step forward, suggesting that combining 2 potent drugs with peginterferon and ribavirin may be highly effective in some of the most challenging patients. More data are needed to clarify whether peginterferon/ribavirin are a necessary component for this patient population or whether interferon-free regimens may be possible.

Stefan Zeuzem, MD: This study and previous studies of alisporivir monotherapy in treatment-naive patients are the only public data we have suggesting that SVR can be possible with interferon-sparing regimens. Three patients with genotype 3 HCV and 1 with genotype 1 HCV have been cured and were cured with alisporivir monotherapy according to data presented to date.[38] The fact that 4 previous null responders achieved SVR with BMS-790052/BMS-650032 dual therapy provides some support for the contention that indeed interferon-sparing regimens are possible.

Paul Y. Kwo, MD: This study provides a glimpse into the future of treatment for null responders. A particularly important issue regarding these findings is that some of the most difficult to treat patients, including some null responders, are people who cannot tolerate peginterferon and ribavirin; these data lend great hope to that substantial population.
Stefan Zeuzem, MD: As yet there are no data regarding predictors of SVR to these regimens for previous null responders. The only predictor that may be assumed at this time is HCV subtype 1b; however, even this assumption is too preliminary. More data from larger trials will be needed before we can determine which patients might be appropriate candidates for an interferon-sparing regimen or whether quadruple therapy would be recommended.

Graham R. Foster, FRCP, PhD: This study provides an exciting start, but it is important to emphasize that these data are very preliminary and involve a very small number of patients. Patients may see these data and expect that 2-drug regimens will be available in the near future; however, even if these data can be confirmed in larger studies, it will be quite some time before such regimens are available. Therefore, patients with cirrhosis certainly cannot afford to wait until that time. Nonetheless, even clinicians with a strong belief in the value of interferon are beginning to consider that interferon may have a more limited future.

March 31, 2011 Investigational Direct-Acting Antiviral BMS-790052 Plus PEG-Interferon Alfa and Ribavirin Achieved Up to 92% Sustained Virologic Response in Phase II Dose-Ranging Study of Treatment-Naive Hepatitis C Patients

EASL 2011-
HCV Cured With out Peginterferon/ribavirin with 2 oral HCV drugs BMS790052+BMS650032: Quadruple Therapy With BMS-790052, BMS-650032 and Peg-IFN/RBV for 24 Weeks Results in 100% SVR12 in HCV Genotype 1 Null Responders: "HCV infection can be cured without interferon & ribavirin: 2 orals BMS790052+BMS650032" - (04/02/11)

Liver Cancer

Two Liver Cancer Discoveries May Impact Hepatitis Patients
Researchers in different countries make two liver cancer discoveries, progress that could have a positive impact on people with advanced chronic Hepatitis B or Hepatitis C.
by Nicole Cutler, L.Ac.
Millions of Americans are currently living with chronic Hepatitis B or Hepatitis C, viral illnesses that can cause significant damage to the liver. Unfortunately, chronic viral hepatitis is the most prominent risk factor for developing hepatocellular carcinoma (HCC), a primary liver cancer. Extraordinarily hard to treat, hepatocellular carcinoma is one of the most perilous types of cancer possible. However, two newly released studies that examined liver cancer on molecular levels could lead to improved treatments - a potential relief to many people with advanced Hepatitis B or Hepatitis C.

Deferoxamine Shows Promise for Liver Cancer in People with Advanced Disease
Deferoxamine, a cancer drug that has an anti-proliferative effect on tumor cells, led to improvement of hepatocellular carcinoma (HCC) in 2 out of 10 patients with moderate-to-severe liver disease, according to a letter in the August 11, 2011, New England Journal of Medicine.

Hepatocellular Carcinoma After Diagnosis of Hepatitis B or C Infection
New Non-Invasive Technology Shows Promise in Shrinking Liver Tumors
Peginterferon Maintenance Therapy in Patients with Advanced Hepatitis C to Prevent Hepatocellular Carcinoma: The Plot Thickens
Watch; RF ablation alternative to surgery in early liver cancer
Metabolic syndrome increases risk of both major types of primary liver cancer


Generic Drug Makers May Soon Pay for Overseas Plant Inspections - ABC News
By (@kimcarollo)
Aug. 16, 2011

VIDEO: One of the world's largest generic drug makers is calling on its fellow manufacturers to help foot the bill for the U.S. Food and Drug Administration to conduct inspections of overseas pharmaceutical plants.

Up to 40 percent of the drugs Americans use are imported, and around 80 percent of the active ingredients in those drugs are made in foreign facilities.
The FDA only inspected 11 percent of the more than 3,700 foreign manufacturing sites in 2009, according to data from the U.S.Government Accountability Office. All manufacturing facilities in the United States, however, are subject to FDA inspection every two years.

Healthy You

The mysteries of belly fat
Health professionals are concerned about belly fat because it can trigger: heart disease, stroke, high blood pressure, diabetes, fatty liver, liver cancer, stress, depression and Alzheimer's. Scientists believe that it is the fat below the surface, called visceral fat, that really does the damage by producing hormones and chemicals that can cause heart disease and more. Also, evidence shows that deep-seated fat near an important vein that leads to the liver can transport fatty acids to the organ.

The result: high blood lipid readings. How do you know when the size of your stomach is putting you in peril? A general guideline is that woman with a waist of more than 35 inches, and a man over 40 inches, could be at more risk. As we age, most people struggle with weight. This is because metabolism slows down causing lean muscle mass to be lost, therefore burning fewer calories.

But there's more: Menopause Typically, women face the menopause phase of their lives sometime between the ages of 45 and 55. It is a profound change where a women's body produces less estrogen and progesterone. One of the results of this can be weight gain, which tends to be around the middle rather than the hips. This shift can begin even before, in the period called perimenopause....Continue reading....

Nearly Everyone Needs a Routine Vitamin D Supplement
By: MITCHEL L. ZOLER, Internal Medicine News Digital Network
NEW YORK – The vast majority of children and adults should receive a routine, daily vitamin D supplement, and this recommendation applies from age 1 year all the way up to age 70 years, Dr. Henry W. Lim said at the meeting.
The only exception is a select group of people at high risk for vitamin D inadequacy who warrant initial testing to be sure they don’t need an even higher starting dosage of the vitamin, said Dr. Lim, professor and chairman of dermatology at Henry Ford Hospital in Detroit.

Only people at risk for vitamin D inadequacy, such as breastfed infants or people with limited sun exposure, should be tested for serum vitamin D level, according to Dr. Henry W. Lim.
Dr. Lim based his recommendations on the revised dietary reference intakes for vitamin D issued by the Institute of Medicine last November, which set a recommended dietary allowance (RDA) of 600 IU/day for ages 1-70 years.
"In my opinion, testing [of serum vitamin D level] should only be done for people at high risk for vitamin D inadequacy," he said. In the group to consider for testing are breastfed infants, older adults with reduced skin synthesis of vitamin D, or people with limited sun exposure, dark skin, fat malabsorption (because vitamin D is fat soluble), or obesity.
"For the average individual [not in a high-risk group] my suggestion is to take 600 IU per day starting at age 1," Dr. Lim said in an interview. At that level, the supplement is relatively innocuous, inexpensive, and addresses the widespread vitamin D inadequacy. He did not rule out routine vitamin D supplements for children younger than 1 year, but noted that the RDA is lower.

Testing a person’s vitamin D level costs about $100, using ICD-9 code 268.9 for unspecified vitamin D deficiency. Doing that for everyone would incur a "tremendous" cost, he said. He also echoed the recent position taken by the American Academy of Dermatology that most vitamin D should come from diet and supplements, and not from sun exposure. "It is inappropriate to recommend intentional exposure to natural or artificial UV [light] for achieving an adequate vitamin D level," he said.

People at high risk for a low vitamin D level need testing to check whether their level falls as low as 10 ng/mL or even 5 ng/mL. With this degree of deficiency, the person might need a single 10,000-IU or even 20,000-IU dose to raise their level quickly. Daily supplements should not exceed 1,000-3,000 IU in children aged 8 years or younger and should not exceed 4,000 IU daily for those aged 9-70 years, Dr. Lim said.

Two types of vitamin D are available in supplement form, D2 and D3 (ergocalciferol and cholecalciferol, respectively). The vitamin D3 form is preferable because it is more effective at raising serum levels, it attaches better to vitamin D–binding protein, and it has a longer shelf life, Dr. Lim said.

He also reviewed the evidence documenting benefit from adequate vitamin D levels. He concurred with the IOM that the best evidence by far to support maintaining a minimum serum vitamin D level involves the vitamin’s effect on skeletal health. For other outcomes, the evidence is "inconsistent, inconclusive, and insufficient to inform nutritional requirements," Dr. Lim said.
Dr. Lim said that he has been a consultant to La Roche-Posay L’Oreal, Clinuvel, and Procter & Gamble and has been an investigator for Clinuvel.

World's Healthiest Foods
Food of the Week: Cucumbers
Sun, 14 Aug 2011 18:39:26


Exercising with Diabetes Complications
Mon, 15 Aug 2011 10:22:49
If you have had diabetes for a long time and have developed complications, you may have questions about whether you should be engaging in physical activity—and if so, what kind of physical activity is best for your condition.

According to Jacqueline Shahar, MEd, RCEP, CDE, a clinical exercise physiologist and manager of Exercise Services in the Joslin Clinic at Joslin Diabetes Center, patients with diabetes complications should definitely continue to find appropriate opportunties for physical activity. In the Joslin’s Easy Start program many patients have significant diabetes complications and are able to exercise regularly and safely as part of their diabetes self-management plan.
There is always some type of exercise people with complications can do. Not remaining activity can lead to developing additional complications and loss of functional capacity (the ability to do the activities of daily living).

Here are some of the more common diabetes complications and recommendations for exercise for each;

Peripheral Neuropathy
Peripheral neuropathy is nerve damage in the extremities, causing tingling, pain or loss of sensation in your toes, feet and fingers. Peripheral neuropathy increases the risk of loss of balance—and subsequently the increased risk of falling. In addition, the pain and burning can make it difficult to walk.
Exercise prescription:
Incorporate balance exercises and avoid weight-bearing activities such as walking or jogging. Good choices are the stationary bike and swimming.

Charcot Foot
Charcot Foot is a specific type of peripheral neuropathy in which there is destruction of the nerves on the bottom of the foot. The foot eventually becomes deformed and loses sensation. It is important to stay off your feet as much as possible.
Exercise prescription:
Use a stationary or arm bike, or do chair exercises using free weights in a seated position.

Proliferative Retinopathy
Proliferative retinopathy is advanced diabetic eye disease in which new, fragile cells develop on the optic disc. These new cells are prone to leakage or hemorrhage into the eye resulting in loss of vision. You may also be at risk for retinal detachment.
Any exercises that increase blood pressure should be avoided. You need to avoid lifting heavy objects and any vigorous exercise. In addition, do not perform any exercise that requires forward bending such as yoga or the valsalva maneuver [The Valsalva maneuver or Valsalva manoeuvre is performed by moderately forceful attempted exhalation against a closed airway, usually done by closing one's mouth and pinching one's nose shut. Variations of the maneuver can be used either in medical examination as a test of cardiac function and autonomic nervous control of the heart, or to "clear" the ears and sinuses (that is, to equalize pressure between them) when ambient pressure changes, as in diving, hyperbaric oxygen therapy, or aviation].
Exercise prescription:
Stick to non weight bearing exercise such as moderate intensity biking or walking in the pool. Or try slow, steady hiking, ballroom dancing or elliptical machines at low to moderate intensity.

Nephropathy is damaged to the kidneys, which eventually leads to complete kidney shutdown and the need for dialysis. With nephropathy, exercise capacity is decreased because of the buildup of waste products in the body.
Exercise prescription:
Light to moderate exercise is encouraged.

Other Issues to Consider When Exercising with Complications
Autonomic (central) neuropathyAutonomic (central) neuropathy can cause significant cardiac changes.The usual heart rate guidelines for exercise don’t apply. Instead use the talk test to determine if you are exercising at an acceptable level. In addition, if you have autonomic neuropathy, you may no longer experience the symptoms of low blood glucose and need to check your blood glucose more frequently.
Foot ulcer or foot deformity—non weight-bearing exercises are preferred as well as keeping the feet clean dry. You should avoid swimming,
The Talk Test
Light intensity exercise—you can sing or whistle while exercising
Moderate intensity exercise—you can talk while exercising
High intensity exercise—you can’t talk
3 Things to Remember When You Exercise with Diabetes!
It is important to check with your health care provider before starting any exercise program.
Always check your blood glucose before and after any exercise routine.
Making an appointment with an exercise physiologist can be very helpful if you have any complications of diabetes.


Hot Weather Takes Toll on Medication
Mon, 15 Aug 2011 21:49:30
The recent heat wave may have taken a toll on your medication. That’s what reporter Walecia Konrad learned after her son’s allergy medication stopped working after being exposed to high temperatures on a family vacation at the lake.
No drug should be exposed to temperatures higher than 86 degrees. Some days the bathroom at our vacation house and certainly the trunk of the car were well above that mark….

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