November 8, 2010

AASLD: Telbivudine Prevents HBV Perinatal Transmission

Bob Roehr

November 8, 2010 (Boston, Massachusetts) — Limited use of telbivudine in highly viremic pregnant women can reduce perinatal hepatitis B virus (HBV) transmission to infants, according to the results of a study presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting. The study was conducted in Nanjing, China, and presented by Calvin Pan, MD, from Mount Sinai Services at Elmhurst Hospital, Mount Sinai School of Medicine in Flushing, New York, on behalf of his colleagues in Nanjing.

Perinatal transmission of HBV is quite common in Southeast Asia and in Asian communities in other parts of the world, even several generations after migration from that region. Despite immunoprophylaxis, HBV transmission continues to occur at rates of 10% to 30% in children born to mothers who are highly viremic, he said.

Previous studies have shown that lamivudine used in the third trimester of pregnancy can significantly reduce HBV transmission. However, the incidence of teratogenicity with telbivudine in animals has restricted its use in pregnant women.

Dr. Pan said the open-label case–controlled study of telbivudine in highly viremic hepatitis B e antigen positive (HBeAg+) mothers was undertaken to assess its efficacy and safety in pregnant women and their offspring. It was the first such study of the drug. A placebo-controlled randomized trial might have raised ethical concerns, given the data on lamivudine. There also was the practical fact that some women knew of and desired prevention intervention and would not have agreed to randomization to placebo.

To participate in the study, the women had to be HBeAg+, have serum HBV DNA levels above 1.0 × 6 log10 copies/mL, and have been screened between 20 and 32 weeks of gestation. It enrolled 95 women who wished to take telbivudine, and a similar number who did not.

Women in the active group received 600 mg/day telbivudine beginning between weeks 20 and 32 of gestation, and continued on it for at least 4 weeks after delivery. Women with elevated alanine transaminase levels had the option of remaining on therapy, and 20% to 30% chose to do so. Physical and laboratory examinations were conducted at baseline, at delivery, and at weeks 4 and 28 after delivery.

"At baseline, both the control arm and the telbivudine arm had HBV DNA of about 8 logs, but at delivery, the mothers in the treatment arm had a tremendous reduction, of about 2.3 logs. About 30% of those on treatment had undetectable [HBV DNA levels]," or less than 1000 copies/mL, said Dr. Pan.

Prior to delivery, HBV DNA levels were 2.35 log10 copies/mL (1.79 standard deviation [SD]) in the treated group, and 7.83 log10 copies/mL (0.67 SD) in the control group (P < .001). The rates of newborns positive for HBV surface antigen (HBsAg+) at birth were 6.32% and 30.43%, respectively (P < .001).

All infants were vaccinated with 200 IU of hepatitis B immunoglobulin within 24 hours of delivery, and with recombinant HBV vaccine 20 μg at birth and at 1 and 6 months. They were tested for HbsAg and HBV DNA at birth and at 28 weeks of age.

At the week-28 end point, according to an intent-to-treat analysis, 2.11% of infants in the active treatment group and 13.04% in the placebo group were either HBsAg+ or had detectible levels of HBV RNA. HBV DNA was only detected in HBsAg+ infants.

Safety proved not to be an issue. There were no discontinuations because of adverse events, and there were no congenital defects that might be attributed to telbivudine.

Anna S. F. Lok, MD, from the University of Michigan in Ann Arbor, congratulated the authors on an excellent study. She asked if there was a threshold level of HBV DNA below which the mother did not transmit virus to the child. Dr. Pan said that analysis on that has not yet been done.

"It's a wonderful study," said Jay H. Hoofnagle, MD, director of the Liver Disease Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland. "I think that randomization is overstressed as an important way to control things. [In this study], you have very nicely balanced groups."

Dr. Hoofnagle said he has no explanation for why the portion of infants who were HBeAg+ or had detectable HBV RNA declined from birth to week 28.

Dr. Pan believes it probably was "a technical issue. We didn't have a very sensitive [polymerase chain reaction] — we were using a cut-off of 1000 — so those patients might simultaneously be DNA-positive."

The Chinese Department of Health underwrote the study with no industry support. None of the physicians have disclosed any relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 212. Presented November 2, 2010.

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Also See: AASLD: Drug Therapy Okay for Pregnant Women With Hep B
Bob Roehr

November 8, 2010 (Boston, Massachusetts) — In March of this year, the US Food and Drug Administration granted a label indication to the antibiotic rifaximin (Xifaxan 550 mg) for the treatment of hepatic encephalopathy. One consequence is a trickle of studies presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting that confirm the efficacy of the drug.

Rifaximin is a potent broad-spectrum antibiotic that has virtually no systemic absorption and is well suited to control intestinal bacterial overgrowth without systemic exposure. Cirrhotic patients are predisposed to intestinal bacterial overgrowth. Deterioration of the gut barrier function can result in the translocation of bacteria and increased abdominal inflammation, which in turn can result in increased portal venous pressure.

Jiannis Vlachogiannakos, MD, and colleagues from the Evangelismos General Hospital in Athens, Greece, conducted a retrospective matched study of patients with alcohol-related decompensated cirrhosis (Child-Pugh score above 7) and ascites. Patients took rifaximin for a short course (4 weeks) and, if they responded with improved liver hemodynamics on hepatic venous pressure gradient testing, were continued on a daily dose of 1200 mg.

The analysis consisted of 23 patients (20 male, 3 female) who took rifaximin, each of whom were sex and age matched (±5 years) to 2 control patients with decompensated cirrhosis of the same etiology who did not take rifaximin. All patients had abstained from alcohol consumption for at least 6 months prior to entering the registry. They were followed for 5 years, death, or liver transplantation, whichever came first.

Dr. Vlachogiannakos said the active group "had a significantly lower risk of developing variceal bleeding (35% vs 59.5%; P = .011), hepatic encephalopathy (31.5% vs 47%; P = .034), spontaneous bacterial peritonitis (5.5% vs 46%; P = .027), and hepatorenal syndrome (4.5% vs 51%; P = .037) than controls."

Patients who did not take rifaximin died in disproportionate numbers (24/46 vs 7/23). He said that "the probability of 5-year survival was 61% in the rifaximin group and 13.5% in the control group (p = .012).

Michael D. Leise, MD, and colleagues from the Mayo Clinic in Rochester, Minnesota, examined medical records from the Mayo Clinic and identified 280 patients with hepatic encephalitis who were given rifaximin on a long-term open-label basis. They compared it with an algorithm of disease state and survival generated from data recorded in the Organ Procurement and Transplant Network.

They found that patients receiving rifaximin generally had better rates of survival, although the difference did not reach statistical significance except in the highest-risk patient group. The authors conclude that in addition to suggesting benefit, it provides assurance on the long-term safety of rifaximin.

Finally, a study from Virginia Commonwealth University in Richmond offered insights into improvement in brain function with rifaximin. Hepatic encephalopathy is associated with driving impairment.

Jasmohan Bajaj, MD, and colleagues used performance on a 15-minute driving-simulator test to evaluate driving and navigation skills (speeding tickets, collisions, and illegal turns) at baseline and 8 weeks after 42 hepatic encephalopathy patients were randomized in a 1:1 manner to receive rifaximin or placebo.

Comparing results from the 2 time points, he found that "76% of patients in the rifaximin group reduced their driving error, compared with only 33% in the placebo group, which is statistically significant." On the speeding ticket criteria, 81% and 33% of the respective groups reduced their errors. But there was no difference between them in terms of collisions, a fact that he attributed to the greater awareness of and learning from a simulated collision.

When asked what physicians might do if they believe a patient is suffering from hepatic-encephalopathy-related cognitive impairment, Dr. Bajaj said the findings are preliminary. More important, "if you have any questions about your patient's driving ability, you are not qualified as a doctor to make that decision. You should send those patients to your department of motor vehicles."

All of the studies were conducted as part of academic research. The researchers have disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstracts 19, 24, and 22. Presented October 31, 2010.

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Also See: AASLD: Antibiotic Reverses Cognition Loss in MHE
Bob Roehr

November 8, 2010 (Boston, Massachusetts) — Proof of concept for the therapeutic vaccine GI-5005 (GlobeImmune) against hepatitis C virus (HCV) infection, used in combination with standard of care (pegylated-interferon alfa-2b plus ribavirin), was presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting. Results were presented by Paul J. Pockros, MD, from the Scripps Clinic in San Diego, California.

One novel approach to treating hepatitis C is to stimulate the immune system to better attack and clear the infection, Dr. Pockros explained. This approach contrasts with most interventions currently in development that use small molecules to directly attack the virus.

The vaccine strategy incorporates HCV nonstructural protein 3 (NS3) and core antigens into recombinant Saccharomyces cerevisiae, a family of budding yeast, and expresses those proteins on the surface of the yeast cell. Dr. Pockros said the mechanism of action is not completely clear, but it is thought that subcutaneous injection of the yeast "stimulates a danger signal, which in turn brings antigen-presenting cells like dendritic cells to the surface."

"Those quickly phagocytose the inactivated yeast. The proteins are broken down, and NS3 and core proteins are expressed on the surface of the dendritic cell. This then stimulates helper and killer T cells," which identify and attack hepatocytes infected with hepatitis C.

"If you give this to patients who are chronically infected, it mimics patients who are acutely infected with HCV — they clear the virus," Dr. Pockros explained. Typically, chronically infected patients do not mount a T cell response against the core, envelop, or nonstructural proteins of HCV, whereas patients who clear the virus "mount a modest response against the envelop proteins and a robust response against nonstructural proteins NS3 and NS5," he added.

The phase 2 study was conducted in 133 patients infected with HCV genotype 1 who were randomized in a 1:1 manner to the vaccine or standard of care. Those assigned to active treatment received 40YU GI-5005 monotherapy (1 YU = 107 yeast particles) 5 times a week, then twice monthly during a 12-week lead-in period before adding standard of care (pegylated-interferon alfa-2b plus ribavirin) and reducing the vaccine dosing to once a month. Treatment-naïve patients followed this regimen for 48 weeks, and nonresponders followed it for 72 weeks. The principle end point was end-of-treatment response/sustained viral response (SVR).

Dr. Pockros said that "there was a slight benefit [from the vaccine] in the treatment-naïve and nonresponders; this was numerical only and was not statistically significant. However, when you added the 2 groups together, it became statistically significant" (P = .037).

Stratifying by IL28B gene status in the standard of care group, 2 of 5 patients with the more difficult to treat T/T allele cleared the virus at some point, but 1 subsequently had viral breakthrough while on therapy, and the second relapsed, "so none of the patients had an SVR."

However, "of the T/T patients who received the vaccine, all 5 cleared the virus. Two had to be taken off therapy because of the side effects of [pegylated-interferon alfa-2b plus ribavirin], but the remaining 3 had a sustained virologic response," according to Dr. Pockros.

He said there was only a modest response among those who were previous virologic nonresponders.

There was a statistically significant difference in those whose alanine transaminase (ALT) levels normalized. "Some of these responses were durable, although this did not quite reach significance" in this study, which was underpowered for subset analysis. Biopsy of 32 patients strongly suggests that the normalization of ALTs seen in some patients "is associated with the reduction in necroinflammation."

Perhaps the most interesting response among those who received the vaccine was the T cell, measured by ELISPOT assay. "It mimicked what you saw with a virologic response," Dr. Pockros said. "Four of 5 T/T allele patients had a T cell response; 1 did not actually get treated. But none of the patients who received standard of care had a T cell response." During the discussion, Dr. Pockros said the vaccine is likely to be genotype specific.

Adverse events mirrored those seen with standard of care, with the addition of some modest reactions at the site of injection for the therapeutic vaccine. The product has currently been administered to more than 250 study subjects.

Session cochair Douglas R. LaBrecque, MD, director of liver services at University of Iowa Health Care in Iowa City, told Medscape Medical News that the data "are so preliminary and in such small numbers that all you can say is it wasn't a total failure."

But he does see a benefit to the approach "if it would allow you to eliminate some of the medications [in a regimen], be it the interferon or small molecules, which have their own side effects."

The private biopharmaceutical company GlobeImmune sponsored the trial. Dr. Pockros reports ongoing research ties with the company. Dr. LaBrecque has disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-6. Presented November 1, 2010.

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Bob Roehr

November 8, 2010 (Boston, Massachusetts) — HIV infection itself appears to negatively affect liver histology, according to research presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting.

Abnormal liver enzymes are common in patients infected with HIV, even in the absence of viral hepatitis or known precipitating factors, such as diabetes or alcohol, but there are few data on the histology that explain why this is so, said Richard K. Sterling, MD, from Virginia Commonwealth University in Richmond, although he added that there has been a suggestion that it might be steatohepatitis.

Dr. Sterling and colleagues undertook a prospective pilot study of liver histology in HIV-positive patients with abnormal liver function tests (>1.25 upper limit of normal in aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase [ALP]), but without viral hepatitis, diabetes, or high levels of alcohol consumption (defined as >30 g/day for males and >20 g/day for females). Of the 25 referred patients, to date, 10 have met the entry criteria for this ongoing study.

Dr. Sterling told Medscape Medical News that he wanted to include ALP "because studies in fatty liver patients have shown that some present only with an isolated ALP. By excluding them, I might be excluding something that's out there."

All patients were receiving highly active antiretroviral therapy (HAART) and most had HIV RNA below the level of detection (<48 copies/mL). It is not known how long the patients have been infected or how long they have been on an antiretroviral regimen, factors that might influence disease state. The sample was too small to stratify by HAART regimens, Dr. Sterling noted.

Of the study population, 70% were male and 60% were white. Average age was 46 years, mean weight was 90 kg, mean body mass index (BMI) was 30 kg/m2, mean waist-to-hip ratio was 0.9 5, mean body fat was 33%, mean abdominal fat was 3652 g, and abdomen-to-gynoid-fat ratio was 1.36.

Patients underwent a 2-hour oral glucose tolerance test, had fasting lipids measured, and underwent dual-energy x-ray absorptiometry for fat distribution at the time of liver biopsy. Insulin resistance (IR) was assessed by homeostatic model assessment (HOMA). All histology was blinded and read by the same person.

"The bottom line is that about 60% had steatosis; 20% had grade 1, 30% had grade 2, and 10% had grade 3 steatosis. Cytologic ballooning was seen in 40%, the nonalcoholic steatohepatitis activity score was 2.7, and 40% had steatohepatitis," Dr. Sterling reported.

He added that the lack of difference in body fat, IR, HAART use, and BMI in the patient population did not surprised him. "If you look at the 4 patients who did not have steatosis but did have abnormal liver enzymes, even though their liver enzymes were lower, they still had hepatic inflammation and a fibrosis score of 1."

"There is something going on there. If it is not fat, what is it? I think it may be oxidative stress and other systemic issues related to HIV or HIV treatment. That is what we are trying to explore," he said.

"This has been a population that has been ignored because everyone is so happy that their HIV is under control," said Dr. Sterling. "Perhaps it will be important to identify patients with steatosis because they have an increased cardiovascular risk — which is the number 3 cause of death [in HIV-positive patients], behind HIV [infection itself] and liver [disease]. There may be a relationship between HIV, steatosis, and cardiovascular disease. It is not something that should be ignored."

Clinical implications might include changing HAART regimen to reduce exposure to drugs associated with IR or steatosis. "If they have steatosis, you might start to screen for cardiovascular disease when otherwise you wouldn't," advised Dr. Sterling. "But we don't know for sure, because no one has looked; you have to identify the problem first."

Raymond T. Chung, MD, director of hepatology at Massachusetts General Hospital, in Boston, cautioned against reading too much into a study of 10 patients receiving HAART. Nucleoside reverse-transcriptase inhibitors and protease inhibitors can either "cause intrinsic hepatotoxicity that may include steatosis, or promote peripheral lipolysis and hepatic steatosis, even without clear-cut increases in HOMA-IR. In this group of patients who were on both sets of agents, one must think of their contribution," he told Medscape Medical News.

However, work in his lab suggests that HIV "appears to exert oxidative stress in hepatocytes, likely through the engagement of chemokine coreceptors found in low levels on those cells. This oxidative stress can contribute to a milieu that may promote steatosis and even fibrosis." Perhaps this is sufficient to trigger hepatic injury, particularly when coupled with other insults such as a mild increase in IR or moderate alcohol use.

The National Institutes of Health sponsored the research under an R03 grant. Dr. Sterling and Dr. Chung have disclosed no relevant financial relationships relevant to this study.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 674. Presented October 30, 2010.

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Study offers new clues to effective HIV vaccine

By Julie Steenhuysen
CHICAGO
Fri Nov 5, 2010 12:27pm EDT

CHICAGO (Reuters) - Slight differences in five amino acids in a protein called HLA-B may explain why certain people resist the human immunodeficiency virus, U.S. researchers said on Thursday in a study that lends new clues about how to make a vaccine to prevent AIDS.

"For a long time, we've known that some people progress extremely rapidly when they get infected, and others can stay well for three decades and never need treatment and still look entirely well," said Dr. Bruce Walker of Massachusetts General Hospital and Harvard University, whose study appears in the journal Science.

"We thought we could apply new techniques from the human genome project to understand what the genetic basis was for that," he said.

About one in 300 people infected with HIV can suppress the virus with the immune system, keeping the virus at extremely low levels.

The team searched the genetic makeup of nearly 1,000 people with that ability and compared it with the genetic code of 2,600 others who were infected with HIV.

That helped them identify some 300 different sites in the genetic code that were linked with immune control of HIV, all located on chromosome 6.

They narrowed that down to four single-letter changes in the DNA, known as single nucleotide polymorphisms or SNPs -- pronounced "snips" -- all related to the immune system.

"We did a second study where we looked amino acid by amino acid in that region," Walker said.

They found five amino acids in the HLA-B protein linked with differences in a person's ability to control HIV.

That protein is important for helping the immune system tag and destroy cells infected by a virus, and Walker said those genetic variants could make a big difference in a person's ability to control HIV.

Knowing how some people mount an effective immune response to HIV could be an important step in understanding how to make a vaccine to fight the virus.

It was not a vaccine yet, Walker cautions, but it is promising.

"We've got a clearer indication of why people can survive in the face of HIV, and we've gotten more focused in terms of the research we need to do to get where we've got to go," he said.

No vaccine exists against the human immunodeficiency virus that causes AIDS. Since the AIDS pandemic started in the early 1980s, almost 60 million people have been infected with HIV, many of them in Africa, and it has killed 25 million.

In September 2009, scientists reported their biggest success yet with an experimental vaccine that showed a modest effect and appeared to slow the rate of infection by about 30 percent. In July, U.S. researchers found antibodies that can protect against a wide range of AIDS viruses and said they may be able to use them to design a vaccine.

(Editing by Peter Cooney)

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Bob Roehr

November 8, 2010 (Boston, Massachusetts) — Treatment of hepatitis C virus (HCV) infection with the protease inhibitor telaprevir added to a standard of care regimen of pegylated interferon alfa-2a plus ribavirin can be shortened from 48 weeks to 24 weeks in patients with an extended rapid viral response (eRVR), according to data presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting.

ILLUMINATE was a multicenter phase 3 open-label study in genotype 1 treatment-naïve patients that used guided duration of treatment to determine the length of the regimen. Principal investigator Kenneth E. Sherman, MD, from the University of Cincinnati College of Medicine in Ohio, delivered the results.

Patients received 12 weeks of telaprevir (750 mg every 8 hours) added to peginterferon alfa-2a (180 μg/week) and weight-based ribavirin (standard of care). Those who achieved an eRVR (undetectable HCV RNA at weeks 4 and 12) were randomized at week 20 to receive an additional 4 weeks or 28 weeks of telaprevir plus standard of care, for a total of 24 or 48 weeks of treatment. Patients who did not meet the eRVR criteria received a standard 48-week course of therapy.

The primary end point was sustained virologic response (SVR) below 25 copies/mL (TaqMan assay) 24 weeks after completion of the regimen. The margin of noninferiority was predefined as –10.5% on intent-to-treat analysis.

Dr. Sherman said stopping rules included discontinuation of telaprevir in those who had HCV RNA levels above 1000 copies/mL at week 4 and continuation of standard of care.

At week 12, "those who failed to achieve at least a 2 log drop from baseline were discontinued on all study drugs and classified as a nonresponders. Between weeks 24 and 36, any patient with a detectable HCV RNA level discontinued all study drugs."

ILLUMINATE involved 540 patients. Of these, 100 discontinued treatment for a variety of reasons before reaching week 20, when randomization was done.

In all, 322 (65%) achieved eRVR (72% on intent-to-treat analysis) and were randomized to either 24 or 48 weeks of telaprevir treatment. SVR was achieved in 92% and 88%, respectively, Dr. Sherman reported.

"There was a positive 4.5% increase in the shorter therapy period; clearly, that was within the noninferiority range," he added. There was no statistical difference between the 2 groups in terms of relapse.

Turning to factors that traditionally predict a poorer response, Dr. Sherman said patients with hepatic fibrosis and cirrhosis showed "quite a respectable 63%" in SVR. "Among those who achieved eRVR, there was no difference between the groups, and no difference between 24 and 48 weeks of therapy," he reported.

There continues to be differences in responses along the lines of race/ethnicity, "but among those who achieved eRVR, there was no difference in response based on race or ethnicity."

Adverse events were those commonly seen in patients treated with the backbone of interferon and ribavirin. Rash attributed to telaprevir was a principle difference, with 63% of patients experiencing some degree of rash and 7% experiencing severe rash. It resolved upon discontinuation or completion of telaprevir. Discontinuation of all drugs for all causes was 7%; rash and anemia each caused 1% of discontinuations.

"Overall, due to any adverse event, 12% discontinued use of telaprevir; rash events constituted 7% and anemia events 2%," he said. There was a 17% discontinuation of all drugs because of adverse events. The rates were similar to those seen in other phase 2 and 3 trials of telaprevir.

Dr. Sherman concluded that there was "no clinical benefit to extending telaprevir-based therapy beyond 24 weeks in patients with eRVR, [which comprised] two thirds of the study patients. All study patients, regardless of liver fibrosis stage, race, or ethnicity, achieved high SVR rates with response-guided therapy."

In response to a question on resistance from the audience, he said that "breakthrough was observed in 1% to 3% of patients who were in the eRVR groups. The resistance patterns are similar to what has been seen previously in patients who do not ultimately clear" the virus, Dr. Sherman responded.

Conference chair Arun Sanyal, MD, from the Medical College of Virginia in Richmond, called the rates of response "incredible when you think about the time when we only had a 5% response rate to interferon." It represents another big step forward in our ability to treat HCV infection, he asserted.

Vertex/Johnson & Johnson sponsored the ILLUMINATE study. Dr. Sherman reports research funding and consulting ties to the company. Dr. Sanyal reports research and consulting ties to other companies developing HCV drugs.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-2 Presented November 1, 2010.

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