April 27, 2012

EASL 2012: Interferon Lambda Beats Alfa in Clearing HCV Genotype 2 or 3


From Medscape Medical News

Daniel M. Keller, PhD

April 27, 2012 (Barcelona, Spain) — In a phase 2b study of treatment-naive adults with chronic hepatitis C virus (HCV) infection, pegylated interferon-lambda was more effective and safer than interferon-alfa in eliminating the virus in patients infected with HCV genotypes 2 or 3. The study is the first report of sustained virologic response with lambda.

Stefan Zeuzem, MD, professor of medicine and chief of the Department of Medicine I at the J.W. Goethe University Hospital in Frankfurt, Germany, who presented the results here at the International Liver Congress 2012, showed data demonstrating that 180 μg of lambda, compared with alfa, produced a more rapid virologic response and a greater sustained virologic response at 24 weeks (SVR24), and was associated with fewer adverse events and less need for a dose reduction of lambda and of the accompanying ribavirin.

Treatment of chronic HCV with alfa interferons and ribavirin is limited by hematologic toxicity and other adverse effects. Lambda has marked activity against HCV and a restricted distribution of receptors in the body, which could make organ systems outside the liver less susceptible to its effects.

Dr. Zeuzem and colleagues performed a blinded randomized study of 526 noncirrhotic treatment-naive HCV-infected adults, 18 to 70 years of age, 118 of whom were chronically infected with genotype 2 or 3 and had HCV RNA levels of at least 100,000 IU/mL. The genotype 2/3 patients received daily ribavirin and weekly doses of lambda 120 μg (n = 29), 180 μg (n = 29), or 240 μg (n = 30) for 24 weeks. Other patients (n = 30) received daily ribavirin plus alfa 180 μg weekly for 24 weeks.

At baseline, the 4 groups were similar in age (range, 48.1 to 50.6 years), sex (range, 52% to 70% male), body mass index (range, 27.8 to 29.0 kg/m²), and viral load (range, 6.42 to 6.66 log10 IU/mL). Most participants were white (range, 76.7% to 89.7%). The proportion of genotype 2 patients was 41.4% in the 120 μg group, 58.6% in the 180 μg group, 53.3% in the 240 μg group, and 50% in the alfa group. A large majority of patients in each group had low liver fibrosis scores.

Lambda Effective With Fewer Adverse Events

Lambda/ribavirin treatment was associated with an early and rapid drop in HCV RNA in a dose-dependent manner. After 2 weeks of treatment, the greatest reductions were seen with the 180 μg and 240 μg doses. All 3 doses of lambda produced more rapid decreases in virus level than alfa/ribavirin. The 180 μg dose will be used going forward in phase 3 trials.

HCV RNA was undetectable at week 4 in 75.9% of patients in the 180 μg group and in 30.0% in the alfa group (P < .05). Complete early virologic response (meaning HVC RNA was detectable at week 4 but not at week 12) and SVR24 were somewhat better with lambda than with alfa, but the difference was not statistically significance. In the lambda groups, 96.6% of patients achieved a complete early virologic response and 75.9% achieved SVR24.

With lambda 180 μg, 70.6% of genotype 2 patients achieved SVR24, as did 83.3% of genotype 3 patients.

Relapse rates, defined as an HCV RNA level of 25 IU/mL or greater during the follow-up period, were low, at about 21% in the lambda 180 μg group and about 25% in the alfa group.

Although all groups experienced a high level of adverse events (in the range of about 95%), some long associated with alfa therapy — "in particular, flu-like symptoms...such as myalgia, arthralgia, pyrexia, and chills" — were significantly lower in the lambda groups (7% to 17% in the 180 μg group) than in the alfa group (20% to 33%). Flu-like symptoms were definitely lower in all 3 lambda groups (20.7% for 180 μg) than in the alfa group (40%), Dr. Zeuzem said, as were musculoskeletal symptoms (20.7% vs 63.3%).

However, the prevalence of psychiatric adverse events (e.g., depression, irritability, or insomnia) was greater in the lambda groups than in the alfa group (41.4% vs 33.3%).

There were no discontinuations because of adverse events in the 180 μg group, but 6.7% dropped out of the alfa group. In the lambda groups, there were dose reductions in lambda or ribavirin at a rate of 6.9% for each; in the alfa group, there were dose reductions at rates of 26.7% for alfa and 43.3% for ribavirin.

Serious adverse events affected less than 4% of patients in the 180 μg and alfa groups. There were no serious adverse events directly related to treatment in the lambda groups.

It has been reported that lambda causes elevations in serum bilirubin, but in this trial at the 180 μg dose, there was only 1 patient (3.4%) with bilirubin elevation (in the range of 1.6 to 2.5 times the upper limit of normal).

There were no reductions in neutrophil or platelet counts associated with any dose of lambda. There were drops in both in the alfa group as long as therapy continued. Low hemoglobin (below 10 g/dL, or a drop of at least 3.4 g/dL), often associated with alfa/ribavirin, occurred in 44.8% of the alfa group and necessitated a ribavirin dose reduction in 23.3% of patients. Hemoglobin levels did not drop as much in the 180 μg group; only 6.9% were classified as having low hemoglobin, and none required a ribavirin dose reduction.

Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University and Hippokration General Hospital in Greece, and a member of the Governing Board Scientific Committee of the European Association for the Study of the Liver (EASL), summarized the findings for Medscape Medical News.

"It seems that the efficacy of interferon lambda might be slightly higher [than alfa], but definitely we can say that the safety profile is better.... The only side effect that was higher, and we cannot explain that, is the psychiatric side effects," he said.

In light of a robust pipeline of oral drugs now in development, Dr. Papatheodoridis said the use of interferons could be fairly limited in the treatment of HCV in the future. "I don't know what role interferon lambda may find when and if it gets licensed. After 2 or 3 years, it is possible that most of the patients will be treated with interferon-free regimens," he explained.

Mark Thursz, MD, professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, and secretary general of the EASL, alluded to this point during a news conference, drawing attention to the safety profile of lambda. Patients receiving ribavirin typically show a drop in hemoglobin, "but there's a smaller drop...in the lambda- than in the alfa-treated patients," he said. "More important are these data on neutrophils and platelets.... You can see no drop in patients who were treated with the lambda interferon.... For patients who still need an interferon and in whom problems with cell counts are going to be an issue, this is a solution."

Dr. Papatheodoridis noted that the bilirubin increase seen with lambda probably does not indicate any damage to the liver, but is perhaps the effect of "this interferon on the enzymes that are involved in the metabolism of bilirubin, which is not very dangerous; it's a lab finding without major clinical significance."

Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX, Janssen, Merck, Novartis, Presidio Pharmaceuticals, Roche, Santaris, and Vertx Pharmaceuticals. Dr. Papatheodoridis and Dr. Thursz have disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 10. Presented April 19, 2012.


Breast-Feeding Past 6 Months Lowers Risk for HIV Transmission

From Medscape Medical News

Ricki Lewis, PhD

April 27, 2012 — Breast-feeding beyond 6 months when mother or infant is taking antiretrovirals (ARVs) can prevent HIV transmission, according to results from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) trial published online April 26 in The Lancet.

Before 2010, the World Health Organization (WHO) and other public health agencies recommended ceasing breast-feeding for HIV-positive mothers in resource-poor countries at or before 6 months to balance the benefits of breast-feeding with the risk of transmitting HIV in milk. However, the newly reported BAN results indicate that once breast-feeding ceases at 6 months, risk for HIV transmission actually increases. In response to this and other studies, WHO guidelines now recommend that HIV-infected mothers of uninfected infants breast-feed for the first year.

Denise J. Jamieson, MD, from the US Centers for Disease Control and Prevention in Atlanta, and the BAN study team randomly assigned mother-infant pairs in Malawi to 3 groups: maternal triple ARVs, infant nevirapine, or no extended postnatal ARVs (controls). Infants were tested for HIV at birth and 2, 12, 28, and 48 weeks. Those infected by 2 weeks were released from the study and treated, as were mothers who progressed to AIDS or had plunging T-cell counts.

Women were instructed to wean between 24 and 28 weeks. At 32 weeks, most of the women in the intervention groups (96%) and in the control group (88%) reported having ceased breast-feeding.

As expected, at 28 weeks, pairs in which 1 member received ARVs had lower incidence of HIV infection than controls. Of the 676 mother-infant pairs in which the mothers took ARVs, 30 infants contracted HIV between 2 and 48 weeks. Of the 680 mother-infant pairs in which infants took nevirapine daily, 25 infants became infected. Of the 542 controls, 38 infants became infected.

"The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI [confidence interval] 5-9) than in the maternal-antiretroviral (4%, 3-6 p=0.0273) or the infant-nevirapine (4%, 2-5; p=0.0027) groups," the researchers write.

The research team collected data from 2004 to 2010. In 2008, noting the increased rate of HIV transmission in the controls, a data safety monitoring board at the National Institute of Allergy and Infectious Diseases recommended that all participants be assigned to an intervention group.

Assessing HIV infection after 28 weeks, when breast-feeding stopped, was revealing: 30% of the infections occurred during that period. Nine were in the maternal-ARV group, 13 in the infant-nevirapine group, and 6 in the control group.

Moreover, adverse events were more frequent during the postweaning period from 29 to 48 weeks, including diarrhea, impaired growth, malaria, tuberculosis, and death.

"The finding that mortality after 28 weeks was significantly higher than before this point (0.120 vs 0.065 per 100 person-weeks; p=0.0070) is cause for grave concern, because mortality rates should decrease with infant age," write Louise Kuhn, MD, Gertrude H. Sergievsky Center, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York City, and Hoosen M. Coovadia, MD, University of Witwatersrand, Johannesburg, South Africa, and University of KwaZulu-Natal, Durban, South Africa, in an accompanying editorial.

A limitation of the study was the inability to draw conclusions about increased risk for adverse events in infants aged 6 to 12 months without also considering a group that continues breast-feeding.

Despite that limitation, Dr. Kuhn and Dr. Coovadia conclude that "[e]arly weaning is neither effective nor safe as an HIV prevention strategy."

Two coauthors received lecture fees from Abbott Laboratories. Another coauthor received free diagnostic kits from Abbott, Roche, Gen-Probe, IQuum, and Perkin-Elmer. The University of North Carolina received grant support from Abbott and GlaxoSmithKline. Dr. Kuhn and Dr. Coovadia have disclosed no relevant financial relationships.

Lancet. Published online April 26, 2012. Abstract Editorial


Bipolar patients can safely and successfully receive interferon-based hepatitis C antiviral treatment

Eur J Gastroenterol Hepatol. 2012 Apr 8. [Epub ahead of print]

Kelly EM, Corace K, Emery J, Cooper CL.

Department of Medicine, The Ottawa Hospital Division of Infectious Diseases Viral Hepatitis Program, University of Ottawa, Ottawa, Canada.


Patients with bipolar disease are often not considered for hepatitis C virus (HCV) antiviral treatment and are excluded from clinical trials because of the risk of interferon-induced exacerbation of their underlying mood disorder. As this risk has not been well quantified in bipolar patients, we evaluated the safety and efficacy of HCV treatment in this population.


A retrospective analysis of HCV patients evaluated at The Ottawa Hospital between January 2000 and February 2008 (n=910) was carried out. Information on demographics, psychiatric history and treatment, baseline liver biopsy and blood work, treatment initiation, adherence, and therapeutic outcomes was collected. This was compared between bipolar patients (B), those with a history of depression (D), and those with no mental health disorders (N).


Of 38 bipolar patients (4.2%), 16 (42.1%) initiated HCV treatment, a rate similar to that in patients with a history of depression (41.4%) and in those without psychiatric illness (32.6%). On-treatment psychiatric complications were comparable between the bipolar and depression groups (B=68.8%, D=54.8%; P=0.29) and were higher than in those without psychiatric illness (N=37.1%; P=0.01). Manic episodes were rare. [B=2 (12.5%), D=1 (0.9%), N=1 (0.7%)]. Interferon dose reduction or discontinuation rates for psychiatric complications (B=12.5%, D=7.9%, N=7.4%; P=NS), completion rates (B=50%, D=69%, N=58%), and sustained virologic response rates (genotype 1: B=33%, D=45%, N=49%) were similar between the groups.


Stable bipolar patients have similar rates of on-treatment psychiatric complications as patients with a history of depression. With pharmacologic intervention and close clinical monitoring, well-selected bipolar patients can successfully complete treatment and achieve outcomes comparable to those in nonbipolar patients.


Hepatitis C virus infects the endothelial cells of the blood-brain barrier

Gastroenterology. 2012 Mar;142(3):634-643.e6. Epub 2011 Dec 1.

Fletcher NF, Wilson GK, Murray J, Hu K, Lewis A, Reynolds GM, Stamataki Z, Meredith LW, Rowe IA, Luo G, Lopez-Ramirez MA, Baumert TF, Weksler B, Couraud PO, Kim KS, Romero IA, Jopling C, Morgello S, Balfe P, McKeating JA.

Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England.


Hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities. However, it is unclear whether such cognitive abnormalities are a function of systemic disease, impaired hepatic function, or virus infection of the CNS.


We measured levels of HCV RNA and expression of the viral entry receptor in brain tissue samples from 10 infected individuals (and 3 uninfected individuals, as controls) and human brain microvascular endothelial cells by using quantitative polymerase chain reaction and immunochemical and confocal imaging analyses. HCV pseudoparticles and cell culture-derived HCV were used to study the ability of endothelial cells to support viral entry and replication.


Using quantitative polymerase chain reaction, we detected HCV RNA in brain tissue of infected individuals at significantly lower levels than in liver samples. Brain microvascular endothelia and brain endothelial cells expressed all of the recognized HCV entry receptors. Two independently derived brain endothelial cell lines, hCMEC/D3 and HBMEC, supported HCV entry and replication. These processes were inhibited by antibodies against the entry factors CD81, scavenger receptor BI, and claudin-1; by interferon; and by reagents that inhibit NS3 protease and NS5B polymerase. HCV infection promotes endothelial permeability and cellular apoptosis.


Human brain endothelial cells express functional receptors that support HCV entry and replication. Virus infection of the CNS might lead to HCV-associated neuropathologies.


Hepatitis E: An emerging disease

Rev Med Interne. 2012 Mar 7. [Epub ahead of print]

Bonnet D, Kamar N, Izopet J, Alric L.

Service de médecine interne, fédération digestive, CHU Purpan, place du Docteur-Baylac, TSA 40031, 31059 Toulouse cedex 9, France.


The hepatitis E virus is endemic in countries with poor sanitation, where it has many similarities with the hepatitis A virus. It causes a strictly human, feco-oral transmitted, acute, self-limited hepatitis in young adults. The outcome is excellent, except in pregnant women and cirrhotic patients, who experience a high mortality rate. The first cases described in industrialized countries were travellers coming from endemic areas. However, there is now growing evidence that locally-acquired hepatitis E is common in these areas, where it is an emergent disease, despite it is still misdiagnosed. In industrialized countries, hepatitis E spreads sporadically and has a predilection for elderly men with comorbidity, particularly chronic liver diseases. The mortality seems to be higher in this population. In these areas, hepatitis E is due to the genotype 3 virus that is thought to be zoonotically transmitted by pigs and wild boar. Hepatitis E may evolve towards a chronic infection in immunocompromised subjects, particularly in solid organ-transplanted patients. In case of chronic infection, it may cause liver fibrosis and cirrhosis. The diagnosis of hepatitis E is based on serological tests (IgM and IgG) and detection of the viral genome by reverse transcription polymerase chain reaction (RT-PCR) on blood and stools. Acute hepatitis E does not require any treatment but in chronically infected patients, a sustained viral response and finally a definitive viral clearance has been observed after a three-month course of low-dose ribavirin (600 to 800mg/day). Two vaccines underwent successful human trials but are not yet commercially available.


Social media: how doctors can contribute


The Lancet, Volume 379, Issue 9826, Page 1562, 28 April 2012


The Lancet

On April 18, The General Medical Council, which regulates medical practice in the UK, opened up its draft guidance on doctors' use of social media for consultation. Comments can be made until June 13, and the results will be published by the end of the year. The guidance emphasises the need to maintain patient confidentiality, provide accurate information, treat colleagues with respect, avoid anonymity online if writing in a professional capacity, be aware of how content is shared, review privacy settings and online presence, declare conflicts of interest, and maintain separate personal and professional profiles.

This conservative approach is not dissimilar to existing guidance from medical associations. Accepting Facebook friend requests from patients is, in general, not advised. But what of situations where doctors and patients are genuine friends? What, too, of the benefits of doctors providing medical information via blogs, Twitter, or Facebook? Current guidance focuses more on the risks than the benefits of doctors' use of social media.

Patients use social networks to research their symptoms, their doctors, their treatments, and to set up support and information groups. Clinicians can use social media to drive awareness, to provide accurate information, and as a portal to communicate with other physicians. An example is the Floating Doctors programme, which uses Facebook and Twitter to ask specialists for clinical advice for patients in remote areas of Central America. Across Africa, the potential for top-quality health information, advice, and access to treatment can be aided by doctors contributing to social media networks. In Taiwan, Facebook use has even contributed to reform of emergency departments.

Much is said about the dangers of social media. Care about posting in a public space is, of course, needed. Doctors, though, should seize the opportunities provided by social networks to improve the health of their patients, and do their utmost to ensure that the highest quality of health information and access to treatment is there for all.