April 22, 2013

Scientists explore mystery of a psychedelic HIV/AIDS drug

By Melissa Healy

April 22, 2013, 3:25 p.m.

For those taking antiretroviral medications for HIV/AIDS, there is one drug in the mix that can put a particular kick in the cocktail: the drug efavirenz, marketed under the commercial names Sustiva and Stocrin, appears to have an "LSD-like interaction" with the receptors in the brain that govern the activity of serotonin, says a study presented in Boston today.

That may explain why roughly half of patients taking efavirenz at the prescribed dose have reported neuropsychiatric side effects that include suicidal depression, night terrors, hallucinations, paranoia, psychosis and delusions. And it may also explain why efavirenz tablets are reportedly being ground up and smoked by drug abusers looking for a hallucinogenic high.

Working with mice, a team led by Dr. John A. Schetz, a pharmacologist from the University of North Texas Health Science Center in Fort Worth, found that efavirenz activates the serotonin 5-HT 2A receptor in the brain, the same molecular site on which lysergic acid diethylamide (LSD) works. Mice that were given efavirenz responded with the same distinctive head-twitching behavior seen when they are given LSD, and mice bred without the serotonin 5-HT 2A receptor do not. And just as they are when under the influence of LSD, mice given efavirenz also were far less bold than would be expected normally when they were allowed to explore an environment filled with unfamiliar sights, smells and objects.

While efavirenz is highly effective in helping suppress the human immunodeficiency virus, its psychoactive potency is weak compared with that of LSD, Schetz said. But if the medication's abuse potential results in increased diversion of the medication to drug abusers, the result could not only be shortages for patients who need it, but the medication's more widespread use could encourage the emergence of strains of HIV that are resistant to efavirenz.

The findings of Schetz's team will be presented this week in Boston at the annual meeting of the Federation of American Societies for Experimental Biology.

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Also See: Recreational use of HIV antiretroviral drug linked to its psychoactivity

Interferon-Free Regimens for Chronic Hepatitis C—A Step Forward

Journal of Clinical & Experimental Hepatology
Volume 3, Issue 1 , Pages 76-78, March 2013

Ajay Duseja

Address for correspondence: Ajay Duseja, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh 160012, India. Tel.: +91 172 2756336; fax: +91 172 2744401.

Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh

Received 1 February 2013; accepted 4 February 2013. published online 11 February 2013.

SECTION EDITOR, Ajay K. Duseja, Chandigarh, India

Abstract 1

Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, Heckaman M, Larsen L, Menon R, Koev G, Tripathi R, Pilot-Matias T, Bernstein B. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med. 2013 Jan 3; 368(1):45–53.

University of Texas Health Science Center at San Antonio, Division of Gastroenterology and Nutrition (MC7878), 7703 Floyd Curl Dr., San Antonio, TX 78229, USA.

Background: There is a need for interferon-free treatment regimens for hepatitis C virus (HCV) infection. The goal of this study was to evaluate ABT-450, a potent HCV NS3 protease inhibitor, combined with low-dose ritonavir (ABT-450/r), in addition to ABT-333, a non-nucleoside NS5B polymerase inhibitor, and ribavirin, for the treatment of HCV infection. Methods: We conducted a 12-week, phase 2a, open-label study involving patients who had HCV genotype 1 infection without cirrhosis. All patients received ABT-333 (400 mg twice daily) and ribavirin (1000–1200 mg per day) and one of two daily doses of ABT-450/r. Groups 1 and 2 included previously untreated patients; group 1 received 250 mg of ABT-450 and 100 mg of ritonavir, and group 2 received 150 mg and 100 mg, respectively. Group 3, which included patients who had had a null or partial response to previous therapy with peginterferon and ribavirin, received daily doses of 150 mg of ABT-450 and 100 mg of ritonavir. The primary end point was an undetectable level of HCV RNA from week 4 through week 12 (extended rapid virologic response).

Results: A total of 17 of the 19 patients in group 1 (89%) and 11 of the 14 in group 2 (79%) had an extended rapid virologic response; a sustained virologic response 12 weeks after the end of treatment was achieved in 95% and 93% of the patients, respectively. In group 3, 10 of 17 patients (59%) had an extended rapid virologic response, and 8 (47%) had a sustained virologic response 12 weeks after therapy; 6 patients had virologic breakthrough, and 3 had a relapse. Adverse events included abnormalities in liver-function tests, fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting.

Conclusions: This preliminary study suggests that 12 weeks of therapy with a combination of a protease inhibitor, a non-nucleoside polymerase inhibitor, and ribavirin may be effective for treatment of HCV genotype 1 infection.

Abstract 2

Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013 Jan 3;368(1):34–44.

New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.

Background: The standard treatment for hepatitis C virus (HCV) infection is interferon, which is administered subcutaneously and can have troublesome side effects. We evaluated sofosbuvir, an oral nucleotide inhibitor of HCV polymerase, in interferon-sparing and interferon-free regimens for the treatment of HCV infection.

Methods: We provided open-label treatment to eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400 mg once daily) plus ribavirin for 12 weeks. Three of these groups also received peginterferon alfa-2a for 4, 8, or 12 weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12 weeks or sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12 weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. We report the rate of sustained virologic response 24 weeks after therapy.

Results: Of the 40 patients who underwent randomization, all 10 (100%) who received sofosbuvir plus ribavirin without interferon and all 30 (100%) who received sofosbuvir plus ribavirin for 12 weeks and interferon for 4, 8, or 12 weeks had a sustained virologic response at 24 weeks. For the other patients with HCV genotype 2 or 3 infection, all 10 (100%) who received sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks had a sustained virologic response at 24 weeks, as did 6 of 10 (60%) who received sofosbuvir monotherapy. Among patients with HCV genotype 1 infection, 21 of 25 previously untreated patients (84%) and 1 of 10 with no response to previous therapy (10%) had a sustained virologic response at 24 weeks. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia.

Conclusions: Sofosbuvir plus ribavirin for 12 weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection.

Comments

Presently the standard of care (SOC) for the patients with chronic hepatitis C (CHC) is either a dual regimen [Pegylated interferon (Peg IFN) + Ribavirin (Riba)] for genotype 2 and 3 infections or a triple therapy (Peg IFN + Riba + Protease inhibitor-telaprevir or boceprevir) for genotype 1 infections.1, 2 Sustained virological response (SVR) at 6 months after the end of treatment with these regimens are close to 75% and are almost similar for genotypes 1,2 and 3 of hepatitis C virus (HCV). Even though there is no change in the SVR rates of genotype 2 and 3 HCV, there has been a major change in patients with genotype 1 HCV infections where the SVR has improved from 40% to 75% with triple therapy in comparison to the dual regimen used earlier.1, 2

In spite of a reasonable good response with the present SOC, there is still a scope of improvement in the treatment of both genotype 1 and non-genotype1 infections of HCV. All patients with CHC are not eligible for interferon treatment as interferon based regimens can only be given to patients who qualify certain minimum criteria. Because of the injection based regimens many patients even refuse the treatment especially because of the side effects and adverse reactions related to the effects of interferon. Some patients are even withdrawn from the treatment because of these adverse events. Because of the issues related to the interferon use in patients with CHC and the ever increasing pool of non-responders and relapsers, there is need for the alternative strategies in the treatment of patients with CHC. Direct anti viral drugs (DAA) and host targeting agents (HTA) which can be used without interferon and act at different phases of viral replication cycle and host targets are one of the recent class of drugs which have shown promising results not only in improving the SVR rates but in also avoiding the other problems associated with interferon use.3

Various groups of DAA are now undergoing clinical trials.3 Earliest of the two NS3/4 A protease inhibitors which have been approved by the Food and Drug Administration (FDA), USA for the use as triple therapy (with Peg IFN and Riba) in genotype 1 patients are the telaprevir and boceprevir (first generation PIs).2 Other drugs in the same group include Danoprevir, Vaniprevir, BMS-650032, ABT-450 and few more. The group of nucleoside/nucleotide polymerase inhibitors include drugs like Sofosbvir, PSI-938, Mericitabine and IDX-184. In the non-nucleoside polymerase inhibitors are the drugs like Filibuvir, Tegobuvir, VX-222, ABT-072 and ABT-333 and among the NS5A inhibitors are drugs like Daclatasvir and GS-5885. HTA includes cyclophilin inhibitors like Alisporivir and SCY-635 and the blockers of micro RNA 122.3 An ideal non-interferon drug for CHC should have high cure rates in all categories of patients (independent of host's and viral characteristics—pan genotype effect), good side-effect profile and it should be an all oral, once-daily regimen with short treatment duration with limited drug–drug interactions (especially with immunosuppressant medications) and should be affordable in all countries. Even though we are far away from such an ideal drug or a combination of such drugs several steps have been made in that direction. Two recent trials (Abstract 1 and 2) published in the recent issue of New England Journal of Medicine are such steps in that direction.4, 5

In one of the trials (Abstract 1), ABT-450, a potent inhibitor of the HCV NS3 protease, has been combined with ritonavir (ABT-450/r) to increase the ABT-450 plasma concentration and half-life, permitting once-daily dosing.4 The study assessed the safety and efficacy of the combination of ABT-450/r and ABT-333 with ribavirin in previously untreated patients with HCV genotype 1 infection and in patients with a null or partial response to previous treatment with peginterferon and ribavirin. The primary end point in this study was the percentage of patients with virologic suppression by week 4 of treatment and sustained suppression through week 12 (eRVR). That end point was met in 28 of the 33 previously untreated patients and in 10 of the 17 patients who had undergone previous treatment. Among the previously untreated patients, there were no virologic failures during treatment or during 48 weeks of follow-up for those who completed treatment. In contrast, 9 of the 17 patients with a null or partial response to previous therapy either had virologic breakthrough or had a relapse by the date of their first follow-up visit after treatment. In most cases, virologic failure was associated with the emergence of variants with substitutions in both NS3 and NS5B, at positions known to confer resistance in vitro to ABT-450 and ABT-333, respectively.4

Even though the results of this study are very encouraging, studies with larger sample size using similar regimens will be needed to confirm these findings in subgroups based on HCV genotype, viral load, race, sex, age, severity of liver disease (cirrhotic Vs non-cirrhotics) and the associated HIV infection. Overall this study suggests the limitation of using all oral regimen in patients with HCV genotype 1 infection with a null or partial response to previous therapy, emergence of variants being the most common reason for virological failure. Whether extending treatment beyond 12 weeks could be of help in these patients need to be studied in separate studies.

Sofosbuvir (formerly known as GS-7977) is a direct-acting nucleotide polymerase inhibitor used as an oral drug for the treatment of CHC. The active triphosphate of nucleotide analogs such as sofosbuvir targets the highly conserved active site of the HCV-specific NS5B polymerase, acting as a non-obligate chain terminator, an effect that is independent of the viral genotype. Hence sofosbuvir is effective against all genotypes and till date no virologic breakthrough has been observed during sofosbuvir therapy. In another article in the recent issue of NEJM (Abstract 2), authors report results from the Electron trial, a multipart, phase 2a study designed to test the safety and efficacy of sofosbuvir and ribavirin in various interferon-sparing and interferon-free regimens for the treatment of patients with HCV genotype 1, 2, or 3 infections.5 Patients with CHC without cirrhosis (serum HCV RNA level, >50,000 IU per milliliter) were enrolled at two centers in New Zealand. Both in the previously untreated and treated patients with HCV genotype 1, 2, or 3 infection, HCV RNA levels declined rapidly after the initiation of treatment. By week 4 of treatment, all 95 patients had an undetectable level of HCV RNA, which was maintained until the end of treatment. All 50 previously untreated patients with HCV genotype 2 or 3 infection who received 8 or 12 weeks of treatment with sofosbuvir and ribavirin, with or without peginterferon alfa-2a, had a sustained virologic response at 24 weeks after treatment. Of 10 patients who received sofosbuvir alone without ribavirin, sustained virologic response was seen in 6 patients. The adverse events that occurred in different groups of patients were generally those associated with peginterferon and ribavirin. No patients discontinued sofosbuvir or ribavirin in any group.5

The uniform response obtained in all groups of patients is remarkable because the eight treatment groups included different patient populations, i.e. patients who had an infection with HCV genotype 1, 2, or 3; treatment naive patients; and previous non-responders to interferon and ribavirin. All 10 patients who received sofosbuvir alone also had an undetectable level of HCV RNA by week 4 of treatment, which was maintained for the duration of treatment but 4 of these patients, had a relapse after the end of treatment. These results suggest that in patients with HCV genotype 2 or 3 infection, ribavirin is required with sofosbuvir for the maintenance of an antiviral response. In patients with HCV genotype 1 infection, there were higher rates of sustained virologic response among treatment naive patients, as compared with non-responders to previous treatment with pegylated interferon plus ribavirin. The absence of viral breakthrough in any patient during treatment in the study confirms that sofosbuvir has a high genetic barrier to resistance.

What we require in India are the interferon free, short duration all oral drugs which are effective against genotype 3, which is the predominant genotype in this country. Though polymerase inhibitors like sofosbuvir have pan genotype effect, other drugs are effective only against genotype 1. The second important issue for us would be cost and thus the affordability and availability of these drugs for the major section of patients with CHC. Other issues which need to be addressed are the drug resistance, efficacy in non-responders and relapsers, drug interactions and their efficacy in patients with cirrhosis and advanced fibrosis. More data is required about efficacy of interferon-free regimens in patients with CHC with respect to the IL-28 genotype and the differences in efficacy between genotype 1a and 1b patients with CHC.

References

Source

HIV Drug Cocktail Protect Hearts of Children With Virus

By Nicole Ostrow

April 22, 2013

Potent cocktails of AIDS drugs appear to protect the hearts of HIV-infected children against the ravages of the virus, according to a study.

Children and teens with HIV who took combinations of at least three antiretroviral medicines had fewer instances of heart disease and damage than kids in an older study who received little to no medicine, according to research today in JAMA Pediatrics. In the early 1990s, children with HIV weren’t treated with AIDS drugs or only received a single medicine.

Before the current treatments, called highly active antiretroviral therapies, or HAART, became available, about half of kids with HIV who died did so because their hearts were damaged, said Steven Lipshultz, the lead study author. The results released today indicate that long-term, or lifelong, use of combination therapies to clear the virus may prevent cardiac harm, researchers said.

“One of the miracles of modern medicine related to HIV is coming up with medicines that can’t eliminate HIV but they dramatically reduce it,” Lipshultz, a professor of pediatrics at the University of Miami Miller School of Medicine, said today in a telephone interview. “In addition to dramatically reducing it, it seems to help have a more healthy heart because there’s less virus and an overall normal immune system in these healthy children.”

Ultrasound Change

Because of heart damaged caused by HIV, doctors have required kids with the virus to undergo routine echocardiograms, or ultrasounds of their heart, Lipshultz said. Today’s study also shows that frequent ultrasounds, which cost more than $1,000, can now be stopped, he said.

“The routine monitoring by echo cardiograms is probably not necessary except for in those who we might have a concern,”he said. The findings also have more practical implications in developing countries where HIV rates are the highest and ultrasounds are not always available, he said.

Researchers in the study looked at 325 children who were HIV positive at birth and received a cocktail of antiretroviral medicines and 189 children who were exposed to HIV but not infected with the disease. They also looked at another 70 HIV-infected children from an older study who didn’t get the drugs.

The condition of the heart in children who received the drug cocktail was “significantly closer to normal” than those kids who were HIV positive and didn’t received the drugs, Lipshultz said.

The researchers are now trying to determine which part of the antiretroviral therapies are the most helpful to the heart and which may cause damage to the heart, he said. They are also reviewing the blood work of these studies to see if they can come up with a blood test to determine heart damage rather than using an ultrasound.

Antiretroviral treatments include Johnson & Johnson (JNJ)’s Prezista, Gilead Sciences Inc. (GILD)’s Truvada, Bristol-Myers Squibb Co. (BMY)’s Sustiva and GlaxoSmithKline Plc (GSK)’s Ziagen.

To contact the reporter on this story: Nicole Ostrow in New York at nostrow1@bloomberg.net 

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

Source

17764_0422_aids_goldsteinp

Rebecca Goldstein / DTH

Duke has a lab that is studying HIV vaccine research, in the Duke Human Vaccine Institute. Brad Lockwood, a research analyst, works in the lab.

By Megan Cassella | The Daily Tar Heel

Updated: 18 hours ago

In 2006, a man walked into a sexually transmitted disease clinic in Lilongwe, Malawi, in search of treatment.

Now, seven years, dozens of blood samples and scores of medical tests later, his unique case is still being studied in search of a scientific discovery he never could have imagined.

When the patient walked into the clinic, UNC researchers stationed there identified in his blood an acute HIV infection, the earliest stage of the disease.

His blood samples were then sent to a laboratory run by scientists from Duke University — and now have led to a discovery published earlier this month that scientists are calling an important step in the path to creating the ever-elusive AIDS vaccine.

“In truth, when we enrolled these patients, we didn’t know we’d find this,” said Dr. Myron Cohen, UNC’s associate vice chancellor for global health, who worked on the study.

“This came as a really fantastic example for the prepared mind.”

Following the ‘road map’ to a cure

When the African patient — referred to throughout the study as CH505 — was first identified with the acute infection, researchers took special interest in his case, hoping to follow the evolution of the virus and the body’s response.

He was enrolled in an intense study that involved taking a series of blood samples, Cohen said.

“By seeing them very frequently, we could understand in tremendous detail what was happening,” he said.

And Dr. Barton Haynes, director of the Duke Human Vaccine Institute and head of the research team, said what happened in this particular patient was quite rare.

Haynes said the response of the immune system in HIV-infected individuals can be compared to an arms race, with each side trying to outdo the other. He said one strain of the virus will initially infect the patient, but as soon as the body creates an antibody response to fight it, the virus has already mutated and the antibody is ineffective.

“In most people, that arms race going back and forth doesn’t lead the antibody in the right direction,” he said. “But in some rare individuals, such as the individual from the UNC clinic in Malawi, the right kind of antibodies are made.”

These antibodies — called broadly neutralizing antibodies — are proteins that work to fight all different variations of HIV, creating a powerful and more effective immune system response against the virus. But few patients have them, Haynes said.

Now that the antibodies have been found early on in one patient, scientists hope they can study this particular case to figure out a way to artificially induce the same response in others.

“The breakthrough is that no one’s ever been able to study how a broadly neutralizing antibody evolved from the beginning,” Haynes said.

“This is the first time that we’ve seen the antibodies that we want to induce, how they develop and what pathways they’re taking,” he said.

Scientists are now attempting to recreate in animals what they saw happen in the patient through a series of immunizations, Haynes said, to try to lead the body to produce the antibodies itself.

“No one has been able to study what happened to the virus in response to it from the beginning, thereby providing a road map for us to follow — and that’s the key,” he said.

“The challenge now is to capitalize on that.”

Marybeth McCauley — senior clinical research manager at Family Health International, which managed the study — said the ultimate goal of creating a vaccine is still far off, but she emphasized that the research now is much more focused.

“There’s a long way to go, but this was an excellent breakthrough,” she said.

“And if anyone is going to do it, it’s going to be Bart and his people.”

Collaborative efforts

The results of this study, which were published earlier this month in Nature magazine, were the culmination of a seven-year, multi-million dollar grant from the Center for HIV/AIDS Vaccine Immunology that led to the establishment of 14 clinical sites around the world.

The grant — which was awarded to Haynes and involved investigators from six different institutes — has contributed to efforts to create a vaccine. But Dr. Charles Hicks, an associate professor at Duke and an investigator at one of the clinical sites involved in the study, said the real success between the two universities started years before the grant even existed.

“We started working together even before (the grant), and that’s what helped us build the relationships we have now,” he said.

Hicks, who has been working with Duke for nearly 20 years, said when he first arrived, the relationship between the schools was different — competitive, not collaborative.

“It was the old zero-sum game,” he said. “The prevailing point of view was that if one institution got something, it meant the other hadn’t gotten it.”

But Hicks said after UNC received money for a grant that Duke had not, the two schools started to evaluate their strengths and consider how they might complement one another.

“Then there was this notion that, ‘You know, combining we’re going to be more than the sum of the two — we’re actually going to be a multiplication of the two,’” he said.

Susan Fiscus, a UNC professor of microbiology and immunology who participated in the study, said the relationship between the two schools has made both of them more successful.

“Competition is good, and you strive for your best if you’re working against some competitor who’s also very good,” Fiscus said.

“But by the same token, working together — and (the project) was a remarkable collection of some of the brightest minds from all around the world putting aside their egos to work together for this common cause — I think it worked out very well.”

Contact the desk editor at university@dailytarheel.com.

Published April 22, 2013 in Duke UniversityCampus

Source

Journal of Viral Hepatitis

G. R. Foster, S. Zeuzem, S. Pianko, S. K. Sarin, T. Piratvisuth, S. Shah, P. Andreone, A. Sood, W.-L. Chuang, C.-M. Lee, J. George, M. Gould, R. Flisiak, I. M. Jacobson, P. Komolmit, S. Thongsawat, T. Tanwandee, J. Rasenack, R. Sola, I. Messina, Y. Yin, S. Cammarata, G. Feutren, K. Brown

J Viral Hepat. 2013;20(4):e115-e123.

Abstract and Introduction
Abstract

Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNα-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNα-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 μg q4wk or Peg-IFNα-2a 180 μg qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (≥15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNα-2a and albIFN 1500 μg; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNα-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNα/ribavirin therapy and commonly persisted for ≥6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research.

Introduction

Therapy with pegylated interferon-alfa (Peg-IFNα) and ribavirin (RBV) has become the standard of care for the treatment of chronic hepatitis C virus (HCV),[1] but it has been associated with a number of adverse events (AEs), including frequent manifestations of dry cough and dyspnoea.[2] Rare, potentially fatal cases of interstitial pneumonitis have been reported with an incidence ranging between 0.3% and 0.03%.[2, 3] Little is known, however, about the chronic effect of IFNα on the lung, and no large-scale prospective study has evaluated the incidence of changes in pulmonary physiology and chest imaging during therapy.

Albinterferon alfa-2b (albIFN) is a fusion polypeptide of recombinant human albumin and recombinant IFNα-2b, with a half-life of ~200 hours and IFNα-like pharmacodynamic properties.[4] Recently, albIFN 900 and 1200 μg injected every 2 weeks in combination with RBV was evaluated in more than 2000 patients and was reported to have similar efficacy to that of Peg-IFNα-2a 180 μg injected once weekly (qwk) for the treatment of chronic HCV.[5, 6] Two cases of progressive interstitial lung disease (ILD; one fatal) occurred with albIFN 1200 μg during the course of those trials. Therefore, systematic investigations of pulmonary function and chest imaging were conducted in the present study that evaluated 3 doses of albIFN administered every 4 weeks (q4wk) compared with Peg-IFNα-2a qwk.[7]

Methods
Patients

A more detailed description of the methods, design and primary results of this trial was published previously.[7] Adult patients with chronic HCV genotype 2 or 3 who had not previously received IFNα therapy were enrolled in the study. Patients with decompensated liver disease or other causes of chronic liver disease, thrombocytopenia (<90 000 platelets/mm3), neutropenia (<1500 neutrophils/mm3), history of moderate–severe psychiatric disease, immunologically mediated disease, uncontrolled thyroid disease, co-infection with hepatitis B virus or HIV, a significant coexisting medical condition, or alcohol or drug dependence were excluded. The hepatologist investigators excluded patients with clinical evidence of preexisting ILD or other clinically severe lung disease.

The institutional review boards of the participating centres approved the study protocol, and all patients provided written informed consent.[7]

Study Design

This phase 2b, randomized, multicenter, active-controlled, open-label, dose-ranging study was conducted at 53 centres in 10 countries between October 2008 and May 2009 (ClinicalTrials.gov Identifier: NCT00759200).[7] Patients enrolled in the study were randomly assigned using a centralized interactive voice response system in a ratio of 4:4:4:3 in blocks of 15, to one of four treatment groups, including three albIFN groups (900, 1200 and 1500 μg q4wk; six injections in each group) and the active control Peg-IFNα-2a (Pegasys, Hoffmann–La Roche Ltd, Basel, Switzerland) group (180 μg qwk; 24 injections), with both agents administered subcutaneously. All patients also received oral RBV (Ribasphere, Three Rivers Pharmaceuticals, Warrendale, PA, USA) 800 mg/d in two divided doses. All patients were treated for 24 weeks, with 24-week follow-up.

The primary objective of the study was to assess the safety and tolerability of the albIFN q4wk regimens.[7] The primary efficacy endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<20 IU/mL) at 24 weeks after therapy.

Pulmonary Evaluations

Spirometry (forced expiratory volume in 1 s [FEV1], forced vital capacity [FVC] and FEV1/FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) testing were conducted at baseline, treatment weeks 12 and 24 (or end of treatment), and 24 weeks posttreatment. For spirometry and DLCO assessments, patients were referred to a local pulmonary function laboratory that was certified by the central pulmonary function laboratory (Biomedical Systems, Saint Louis, MO, USA) prior to study initiation. Spirometry and DLCO tests were standardized according to American Thoracic Society/European Respiratory Society guidelines,[8,9] and DLCO was corrected for haemoglobin (see details in Supporting Information Data S1). Data were transferred from the local pulmonary function laboratory to the central laboratory, where they were read for quality control purposes and processing prior to being transferred to the study sponsor.

To confirm the abnormalities, spirometry was repeated within 2 weeks for patients with: (i) a ≥ 10% FVC decrease from baseline, if baseline FVC was <80% of the predicted value; (ii) an FVC reduction to <80% of predicted, if baseline FVC was normal (≥80% of predicted); or (iii) a ≥ 10% decrease in FEV1/FVC from baseline. Spirometry and DLCO were repeated within 2 weeks for patients with: (i) a ≥ 15% DLCO decrease from baseline, if baseline DLCO was <80% of the predicted value or (ii) a DLCO reduction to <80% of predicted, if baseline DLCO was normal (≥80% of predicted). These thresholds for reduced absolute values and declines in spirometry and DLCO are considered clinically relevant abnormalities in the context of ILD and therefore were used also to categorize spirometry and DLCO data in the statistical analyses.[10, 11]

Chest X-rays (CXRs; postero-anterior and lateral views) were obtained at baseline and week 24 (or end of treatment). Chest x-rays were read centrally (RadPharm, Princeton, NJ, USA), and abnormal CXRs were reviewed by an independent radiologist (Prof David Lynch, National Jewish Health, Denver, CO, USA). Routine computed tomography of the chest was not included in the study protocol due to ethical concern and several country regulations prohibiting unnecessary X-ray exposure. Clinical AEs were coded according to the Medical Dictionary for Regulatory Activities, with severity graded using the Division of Microbiology and Infectious Diseases toxicity rating scale.[12]

Statistical Methods

Sample size was chosen based on the power to detect treatment-related AEs, rather than statistical power for hypothesis testing.[7] A minimum of 100 patients per albIFN treatment group and 75 in the Peg-IFNα-2a control group were targeted to be randomized and treated in this study to provide >80% power to detect an AE occurring at an actual rate of 2%.

All analyses were performed in the intention-to-treat population with all available data (including spirometry and DLCO retesting), using SAS 9 statistical software (SAS Institute Inc., Cary, NC, USA). All statistical tests were two-sided and performed at the 5% level of significance. No adjustment was made for multiple comparisons. Likelihood ratio test (or Fisher's exact test when >20% of expected contingency table cell counts were <5) was used for categorical variable comparisons, and analysis of variance was used for continuous variable comparisons. A logistic regression model was built to investigate the relation between DLCO decline (≥ vs <15%) and disease characteristic covariates.

Role of the Funding Source

Novartis Pharma AG (Basel) sponsored the study, which was cofunded by Human Genome Sciences (Rockville, MD, USA).[7] Novartis was responsible for collection and statistical analysis of the data and contributed to patient recruitment, trial management and writing and review of the report. A trial steering committee comprising study investigators provided input to the protocol and oversight of the conduct of the study, and an independent data monitoring committee was responsible for ongoing review of safety data during the study. The corresponding author had final responsibility for the decision to submit for publication. The authors had full access to the data, wrote this manuscript and take accountability for the accuracy of the reported analysis.

Results
Patient Disposition, Demographics and Virologic Response

In all, 391 patients were randomly assigned, and 388 received at least one dose of study drug.[7] There were 2 (3%), 5 (5%), 7 (7%) and 7 (7%) patients who did not complete the study in the Peg-IFNα-2a 180-μg qwk and albIFN 900-, 1200-, and 1500-μg q4wk arms, respectively, due to AEs, failure to achieve an early virologic response at week 12, patient request or being lost to follow-up. Patient demographics and disease characteristics were similar across treatment groups. Overall, 278 patients (72%) had HCV genotype 3, and 110 (28%) had genotype 2. Baseline spirometry, DLCO measurements and chest imaging abnormalities were generally similar across groups; exceptions included FEV1 with albIFN 1200 μg, and FVC with albIFN 1200 and 1500 μg, which were lower than with Peg-IFNα-2a ( ). Current smoking was reported by 29% of patients. Of the 343 patients with baseline spirometry, assessments showed values <80% of the predicted value for FEV1 in 11% of patients, for FVC in 6% and for DLCO in 27%. Based on American Thoracic Society spirometry categories,[13,14] 2% of patients showed physiologic obstruction at baseline (all with ongoing asthma or chronic obstructive pulmonary disease at baseline) and 6% were potentially restricted. Of the 387 patients with a baseline CXR, lung abnormalities were found in 5 (1%); 4 had interstitial findings, and 1 had consolidation.

Table 1. Demographic and baseline characteristics

All (N = 388) albIFN Peg-IFNα-2a180 μg qwk(n = 78)
900 μg q4wk (n = 102) 1200 μg q4wk (n = 103) 1500 μg q4wk (n = 105)
Men 238 (61) 66 (65) 65 (63) 57 (54) 50 (64)
Race
Asian 202 (52) 53 (52) 60 (58) 50 (48) 39 (50)
White 174 (45) 46 (45) 41 (40) 51 (49) 36 (46)
Black 4 (1) 0 1 (1) 2 (2) 1 (1)
Other 8 (2) 3 (3) 1 (1) 2 (2) 2 (3)
Mean age, year (SD) 42.4 (11.8) 42.2 (12.4) 43.2 (12.0) 41.3 (11.3) 43.3 (11.4)
Age ≥45 years 177 (46) 43 (42) 46 (45) 46 (44) 42 (54)
Pulmonary history
Current smoker 113 (29) 29 (28) 33 (32) 32 (31) 19 (24)
Ongoing respiratory disorders at baseline 46 (12) 9 (9) 11 (11) 14 (13) 12 (15)
Mean FEV1, % predicted (SD) 99.8 (15.9) 100.8 (15.6) 97.7 (15.7) 98.4 (15.4) 102.7 (17.1)
FEV1 <80% of predicted 36 (11) 9 (10) 11 (12) 11 (12) 5 (7)
FVC, % predicted (SD) 103.7 (16.2) 105.7 (16.0) 101.9 (17.2) 101.1 (14.1)# 106.9 (17.3)
FVC <80% of predicted 20 (6) 3 (3) 7 (8) 8 (9) 2 (3)
Mean FEV1/FVC ratio (SD) 79.6 (7.6) 78.7 (6.4) 79.9 (8.4) 80.6 (7.1) 78.7 (8.2)
Normal* 315 (92) 87 (96) 79 (90) 84 (89) 65 (93)
Obstructed 8 (2) 1 (1) 2 (2) 2 (2) 3 (4)
Potentially restricted 20 (6) 3 (3) 7 (8) 8 (9) 2 (3)
Obstructed and potentially restricted§ 0 0 0 0 0
Baseline DLCO (% predicted, corrected for haemoglobin), n 363 98 95 97 73
Mean DLCO (SD) 90.0 (15.6) 90.8 (14.6) 89.1 (17.1) 89.3 (14.3) 90.8 (16.9)
DLCO <80% of predicted 98 (27) 21 (21) 30 (32) 26 (27) 21 (29)
Baseline CXR, n 387 101 103 105 78
Any lung abnormality 5 (1) 0 3 (3) 0 2 (3)

Data are number (%) unless noted. albIFN, albinterferon alfa-2b; CXR, chest X-ray; DLCO, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; Peg-IFNα-2a, pegylated interferon alfa-2a. *Normal defined as FEV1/FVC ratio ≥80% and FVC ≥80% of predicted value. Obstructed defined as FEV1/FVC ratio <80% and FVC ≥80% of predicted. Potentially restricted defined as FEV1/FVC ratio ≥80% and FVC <80% of predicted. §Obstructed and potentially restricted defined as FEV1/FVC ratio <80% and FVC <80% of predicted. P = 0.048 vs Peg-IFNα-2a 180 μg qwk. P = 0.051 vs Peg-IFNα-2a 180 μg qwk. #P = 0.02 vs Peg-IFNα-2a 180 μg qwk.

At the end of treatment, rates of undetectable HCV RNA were in the range of 89% to 96% across treatment groups.[7] At the end of posttreatment follow-up, SVR rates were 85%, 76%, 76% and 78% with Peg-IFNα-2a 180 μg qwk and albIFN 900, 1200 and 1500 μg q4wk, respectively (all P = NS).

Respiratory Adverse Events and Chest X-rays

Respiratory AEs were reported by 42% of patients. Four cases of pneumonia and one of restrictive pulmonary disease (dyspnoea and reduced DLCO) were reported as serious AEs in the albIFN groups, with no serious respiratory AEs reported in the Peg-IFNα-2a group (). The case of serious restrictive pulmonary disease occurred in the albIFN 1500-μg q4wk group and was characterized by dyspnoea that was reported at month 1 and worsened by month 3, requiring hospitalization. At baseline, this patient was asymptomatic with normal spirometry and DLCO, but with interstitial findings on CXR. By month 3, DLCO had declined by 66%, with FVC suggestive of restrictive lung disease, and interstitial findings on CXR and chest computed tomography, but in the absence of lung biopsy, there was no confirmed diagnosis of ILD. Dyspnoea resolved after treatment discontinuation and pulmonary function tests improved. No definitive case of ILD was reported by the principal investigators on site.

Table 2. Incidence of respiratory adverse events and infections

All (N = 388) albIFN Peg-IFNα-2a 180 μg qwk (n = 78)
900 μg q4wk (n = 102) 1200 μg q4wk (n = 103) 1500 μg q4wk (n = 105)
Respiratory AE 164 (42) 4 (46) 3 (37) 46 (44) 3 (42)
Serious respiratory AE 2 (1) 1 (1) 0 1 (1) 0
Respiratory AE leading to discontinuation of IFN or RBV 3 (1) 1 (1) 0 1 (1) 1 (1)
Common respiratory AE (n ≥ 5)
Cough 93 (24) 24 (24) 22 (21) 31 (30) 16 (21)
Dyspnoea 44 (11) 14 (14) 8 (8) 15 (14) 7 (9)
Dyspnoea exertional 27 (7) 6 (6) 9 (9) 4 (4) 8 (10)
Productive cough 22 (6) 4 (4) 8 (8) 7 (7) 3 (4)
Oropharyngeal pain 20 (5) 5 (5) 7 (7) 3 (3) 5 (6)
Epistaxis 11 (3) 3 (3) 4 (4) 2 (2) 2 (3)
Obstructive airways 5 (1) 3 (3) 0 2 (2) 0
Throat irritation 5 (1) 0 1 (1) 2 (2) 2 (3)
Serious LRTI 4 (1) 3 (3) 1 (1) 0 0
LRTI leading to discontinuation of IFN or RBV 1 (0) 0 0 0 1 (1)
LRTI 10 (3) 5 (5) 2 (2) 2 (2) 1 (1)
Pneumonia 4 (1) 3 (3) 1 (1) 0 0
Bronchitis 2 (1) 0 0 1 (1) 1 (1)
Other (unspecified) 4 (1) 2 (2) 1 (1) 1 (1) 0

Data are number (%). No statistically significant difference in any group. AE, adverse event; albIFN, albinterferon alfa-2b; IFN, interferon; LRTI, lower respiratory tract infection; Peg-IFNα-2a, peginterferon alfa-2a; RBV, ribavirin.

Respiratory AEs led to treatment discontinuation in 3 patients, 2 receiving albIFN (pneumonia in the 900-μg q4wk group and restrictive lung disease with exertional dyspnoea in the 1500-μg q4wk group) and 1 with exertional dyspnoea in the Peg-IFNα-2a 180-μg qwk group; these AEs reversed after the end of treatment. The most frequently noted respiratory AEs were cough (24%) and dyspnoea (11%), and there was no significant difference among treatment groups. Cough and dyspnoea, which were reported as early as 2 weeks after the start of treatment with their prevalence peaking at weeks 10–12, were reversible in most patients by 12 weeks after treatment.

Changes in Pulmonary Function on Treatment

Over the entire study duration, changes were seen in both spirometry and DLCO. The mean maximum reduction (SD) in FEV1 was 7.3% (12.1%), FVC fell by 5.9% (8.0%), and FEV1/FVC decreased by 2.6% (4.6%). Maximum declines were observed at treatment week 12 (Fig. 1). Absolute declines ≥10% from baseline occurred in 89 patients (26%) for FEV1, 78 (23%) for FVC and 10 (3%) for FEV1/FVC. The presence of symmetric declines in FEV1 and FVC combined with a normal FEV1/FVC is suggestive of mild pulmonary restriction.

781495-fig1

Figure 1.

Left panels, mean absolute changes from baseline in percent of predicted values; right panels, percent of patients with absolute decline in percent of predicted values. albIFN, albinterferon alfa-2b; DLCO, diffusing capacity of the lung for carbon monoxide; FEV 1, forced expiratory volume in 1 s; FVC, forced vital capacity; Peg-IFNα-2a, peginterferon alfa- 2a. *P < 0.05 for comparison between albIFN and Peg-IFNα-2a treatment arms

The maximum DLCO decline (mean change [SD] from baseline of the percent predicted absolute value, corrected for haemoglobin) was 15.4% (11.2%) and was similar across all treatment groups; as with the changes in spirometry, the maximum decline was observed at treatment week 12 (Fig. 1). In all, 173 patients (49%) had a DLCO decline ≥15%—a value considered clinically relevant—and 32 (9%) had a decline ≥30%. At baseline, 27% of patients had a reduced DLCO (absolute DLCO <80% of predicted), while on treatment, 249 patients (65%) had a reduced DLCO and 13 (3%) had a severe DLCO reduction (≤50% of predicted), with no statistically significant difference between treatment groups. Of 13 patients with DLCO <50% of predicted, 1 had a serious pulmonary AE of restrictive lung disease (as described previously).

In general, no significant differences were found across treatment groups for changes in DLCO or spirometry, with the exceptions of a greater mean decline (SD) in FEV1 with albIFN 1200 μg q4wk than with Peg-IFNα-2a 180 μg qwk at treatment week 24 (−4.3 [8.8] vs −0.8 [8.5]; P = 0.01), and fewer patients with a DLCO decline ≥15% with albIFN 900 and 1200 μg than with Peg-IFNα-2a at week 12 (21 [26%] and 19 [25%] vs 25 [42%]; P = 0.04 and 0.03, respectively; Fig. 1).

No significant association was found between DLCO decline ≥15% vs <15% and the incidence of any respiratory AEs (77/172 [45%] vs81/184 [44%]), cough (42/172 [24%] vs 47/184 [26%]) or dyspnoea (17/172 [10%] vs 26/184 [14%]).

Pulmonary Function in Posttreatment Period

Pulmonary function changes were largely reversible by 24 weeks posttreatment, but clinically relevant declines from baseline persisted in 57/315 patients (18%) for DLCO (≥15% decline), 39/302 (13%) for FVC (≥10% decline) and 40/302 (13%) for FEV1 (≥10% decline; Fig. 1). These persistent abnormalities were statistically significant for FVC with albIFN 1200 μg q4wk vs Peg-IFNα-2a 180 μg qwk (13/77 [17%] vs4/66 [6%]; P = 0.046) and were numerically more frequent for DLCO with albIFN 900 and 1200 μg vs Peg-IFNα-2a (17/81 [21%] and 17/80 [21%] vs 9/69 [13%], respectively).

Predictive Factors of DLCO Declines on Treatment

Multivariate analysis of baseline and treatment factors showed a greater risk of DLCO decline ≥15% at treatment week 12 to be associated with higher baseline DLCO (% predicted, corrected for haemoglobin) and treatment with albIFN 900 and 1200 μg q4wk compared with Peg-IFNα-2a 180 μg qwk (). At 24 weeks posttreatment, a greater risk of persistent DLCO decline ≥15% from baseline was associated with female gender and Asian region (but not body mass index), higher baseline DLCO and lesser DLCO decline at treatment week 12. Smoking was not a risk factor for DLCO decline on treatment or posttreatment. Likewise, neither baseline HCV RNA ≥800 000 IU/mL nor SVR was associated with decline in DLCO.

Table 3. Multivariate logistic regression of DLCO decline (≥ vs <15%) at week 12 on treatment and at week 24 posttreatment, and impact of demographic and disease characteristics

Parameter Parameter estimate SE Odds ratio (95% CI) P-value
Week 12 DLCO decline on treatment (≥ vs <15%)
Intercept −6.3703 1.0329
<0.001
Treatment: albIFN 1500 μg q4wk 0.0044 0.3803 1.00 (0.48, 2.12) 0.99
Treatment: albIFN 1200 μg q4wk −0.8172 0.4112 0.44 (0.20, 0.99) 0.046
Treatment: albIFN 900 μg q4wk −0.9264 0.4031 0.40 (0.18, 0.87) 0.02
Baseline DLCO % predicted corrected for haemoglobin 0.0668 0.0108 1.07 (1.05, 1.09) <0.001
Week 24 posttreatment DLCO decline (≥ vs <15%)*
Intercept −8.232 1.5332
<0.001
Gender (male vs female) −1.1605 0.4126 0.31 (0.14, 0.70) 0.005
Region (Asian vs non-Asian) 1.0451 0.4108 2.84 (1.27, 6.36) 0.01
DLCO decline % predicted corrected for haemoglobin at week 12 −0.0859 0.0201 0.92 (0.88, 0.95) <0.001
Baseline DLCO % predicted corrected for haemoglobin 0.0578 0.0161 1.06 (1.03, 1.09) <0.001

The covariates tested included treatment group (albinterferon alfa-2b [albIFN] 900, 1200, and 1500 μg q2wk vs pegylated interferon alfa-2a 180 μg qwk); age (≥ vs <45 years); gender (male vs female); genotype (2 vs 3); weight (≥ vs <75 kg); body mass index (≥ vs <25 kg/m2); smoking status (current vs not current); alcohol use (history vs no history); baseline alanine aminotransaminase (> vs ≤1.5x upper limit of normal); baseline γ-glutamyl transpeptidase (> vs ≤ upper limit of normal); region (Asian vs non-Asian); baseline hepatitis C virus RNA (≥ vs <800,000 IU/mL); hepatitis C virus disease duration (years); pulmonary history (history vs no history); and baseline forced expiratory volume in 1 s (FEV1), baseline forced vital capacity (FVC %), baseline FEV1/FVC and baseline diffusing capacity of the lung for carbon monoxide (DLCO). *Additional variables included were sustained virologic response (yes vs no); FEV1, FVC % and FEV1/FVC at week 12; and DLCO decline at week 12.

Genetic variation of the interleukin 28B single nucleotide polymorphisms rs12979860 has been shown to be associated with virologic response to IFN in patients with chronic HCV.[15] In this study, the interleukin 28B genotype was measured in a subgroup of 117 patients and was not found to be associated with DLCO decline.

Discussion

Long-acting IFN therapy forms the backbone of current treatment for patients with chronic HCV, and many thousands receive these therapies every year. Overt ILD is a rare, but well-known complication of IFN therapy for chronic HCV.[16, 17] Systematic investigations of pulmonary function during IFN therapy to assess any subclinical changes in pulmonary function and to determine whether these changes predict the risk of ILD on treatment have not, however, been conducted. The occurrence of two cases of ILD with albIFN treatment in a previous trial led to the systematic and standardized evaluation of pulmonary function in the present study.[6]

To ensure the quality of the pulmonary function tests across the 53 hepatology centres involved in this study, local pulmonary laboratories were certified prior to testing patients and the quality of the individual tests was reviewed prior to validating the results. The absence of standard pulmonary function test values for the populations of several countries in the study created a limitation to the detection of mildly abnormal absolute spirometry values and to the categorization of those values into obstructed, potentially restricted or mixed patterns. Further, the calculation of DLCO is strongly dependent on haemoglobin level, and a drop in haemoglobin is a common occurrence during RBV therapy. This factor was, however, accounted for by a thorough adjustment of DLCO to the actual haemoglobin level at the time of the test.

Despite these limitations and the lack of an untreated placebo control, the magnitude and consistency of DLCO changes from baseline in all treatment groups, including the widely used Peg-IFNα-2a, and the reversibility of changes after the end of treatment support an effect of IFNα and RBV treatment. The changes in FVC combined with the stability of the FEV1/FVC ratio—although modest—further support the hypothesis of mild restrictive pulmonary changes and reductions in lung diffusion capacity during treatment. These functional changes were not associated with an increased incidence of respiratory symptoms, such as cough and dyspnoea, and did not appear to be associated with major radiologic lung abnormalities, as only one case of interstitial lung findings was observed by CXR at the end of the treatment period. Systematic high-resolution chest computed tomography—a more sensitive method than CXR for detection of interstitial lung changes—was not included in the trial to avoid unnecessary exposure of patients to radiation.

Spirometry and DLCO measurements declined on treatment weeks 12 and 24 when most patients had undetectable HCV RNA; therefore, the pulmonary changes were unlikely to be related to HCV. In multivariate analyses, baseline HCV RNA level and SVR were not associated with DLCO decline, suggesting that virologic factors did not influence respiratory function. The only baseline factor significantly associated with DLCO decline on treatment was baseline DLCO, although the magnitude of the effect was small. Smoking status did not appear to be a significant factor for DLCO decline on treatment or posttreatment. The risk of persistent DLCO decline was almost three times higher in Asian than in white patients. This high frequency, combined with the large number of patients enrolled in the Asian region, may have contributed to the high rate of DLCO declines observed in this trial.

Cough and dyspnoea are common AEs in patients receiving Peg-IFNα and RBV therapy. In this study, these AEs occurred early and were frequent in all treatment groups and were rapidly reversible after the end of treatment; declines in DLCO or spirometry measurements did not appear to be associated with these AEs. The absence of an association between cough and decline in pulmonary function is consistent with recent findings that cough during IFNα/RBV therapy may be related to an increased sensitivity of the cough reflex.[18]

In conclusion, this study revealed the frequent occurrence of DLCO declines of clinically relevant magnitude (≥15% from baseline) during the treatment of chronic HCV with modified IFNα and RBV. These pulmonary changes persisted in some patients for 6 months after the end of treatment, but did not appear to be associated with an increased frequency of respiratory AEs. The potential mechanisms and implications for the risk of developing ILD on HCV treatment, and for long-term pulmonary function after treatment, warrant further research. At present, however, we suggest that patients with HCV who develop severe dyspnoea during IFN therapy should have their respiratory function checked, in particular those who have a preexisting chronic pulmonary disease or CXR abnormalities, and should be referred for pulmonary consultation in case of clinically relevant reductions in pulmonary function tests.

References
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  6. Zeuzem S, Sulkowski MS, Lawitz EJ et al; for ACHIEVE-1 Study Team. Albinterferon alfa-2b was not inferior to pegylated interferon-a in a randomized trial of patients with chronic hepatitis C virus genotype 1. Gastroenterology 2010; 139: 1257–1266

  7. Pianko S, Zeuzem S, Chuang WL et al. Randomized trial of albinterferon- alfa-2b every four weeks for genotype 2/3 chronic hepatitis C. J Viral Hepat 2012; 19: 623–634

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Acknowledgements

Lead investigators: Australia: Crawford D, Desmond P, George J, Pianko S, Sasadeusz J, Weltman M; Canada: Anderson F, Fournier C, Gould M, Swain M, Wong F, Yoshida E; Germany: Berg T, Buggisch P, Gerken G, Goeser T, Rasenack J, Zeuzem S (principal investigator);India: Habeeb A, Kapoor D, Kar P, Prabhakar B, Sarin S, Shah S, Sood A; Italy: Andreone P, Brunetto M, Craxi A, Mondelli M, Rizzetto M;Poland: Flisiak R, Jablkowski M; Spain: Andrade R, Barcena R, Buti M, Castellano D, Diago M, Perez R, Romero M, Sola R; Taiwan: Chang T, Chuang W, Kao J, Lee C; Thailand: Komolmit P, Piratvisuth T, Sukeepaisarnjaroen W, Tanwandee T, Thongsawat S; United Kingdom: Brown A, Cramp M, Foster GR, Mills P; United States: Jacobson I, Bain V.

J Viral Hepat. 2013;20(4):e115-e123. © 2013 Blackwell Publishing

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Hepatitis C-like Viruses Identified in Bats and Rodents

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Discovery opens avenues to developing new treatments

As many as one in 50 people around the world is infected with some type of hepacivirus or pegivirus, including up to 200 million with hepatitis C virus (HCV), a leading cause of liver failure and liver cancer. There has been speculation that these agents arose in wildlife and jumped species to infect humans; however, little was known about their distribution in other species.

In two new papers published in the journals mBio and Proceedings of the National Academy of Sciences, investigators at the Center for Infection and Immunity (CII) report the discovery of hepaciviruses and pegiviruses—close relatives of HCV—in rodents and bats. The viruses are similar to those that infect humans and may therefore provide insights into the origins of HCV, as well as the mechanisms behind animal-to-human transmission. It may also enable development of new animal systems with which to model HCV pathogenesis, vaccine design, and treatment.

Both discoveries were made using high-throughput sequencing and other molecular methods for pathogen discovery pioneered at CII. Both represented multicenter global efforts.

As reported in mBio, Amit Kapoor, PhD, and colleagues screened more than 400 wild-caught rodents. Molecular analysis revealed the presence of hepaciviruses and pegiviruses closely related to those found in humans. “Importantly, the rodent hepaviviruses contained sequences that are thought to play a role in liver infection in HCV,” says Dr. Kapoor, lead author of the study and assistant professor of Pathology and Cell Biology at Columbia University Medical Center. “We also found instances of a single animal infected with multiple hepaciviruses.”

Such co-infections have also been observed with HCV in humans, suggesting that the immune response to HCV is different than with most viral infections—a finding that has implications for vaccine design. “It also supports the potential use of rodent hepaciviruses in developing models for human disease,” says W. Ian Lipkin, MD, John Snow Professor of Epidemiology and director of the CII.

Researchers from Rockefeller University, University of Edinburgh, University of Copenhagen, University of New Mexico, North Carolina College of Veterinary Medicine, Pennsylvania State University and the National Institutes of Health contributed to the study. Results appear online in mBio.

In a second study led by P. Lan Quan, PhD, molecular assays of 1,615 bats collected worldwide led to the identification of 83 novel hepaciviruses and pegiviruses, representing an infection rate of nearly 5%. “The broad prevalence, unprecedented diversity, and worldwide distribution of these novel viruses suggest that bats are a major and ancient reservoir for both hepaciviruses and pegiviruses, and provide insights into the evolutionary history of HCV and human pegiviruses,” says Dr. Quan, associate research scientist at the Center for Infection and Immunity.

Researchers from EcoHealth Alliance, Centers for Disease Control, University of Pretoria, University of Kinshasa, Universidad Nacional Autónoma de México, Ahmadu Bello University, Universidad del Valle de Guatemala, University of Kisangani, National Museum of Kenya, and the University of Sydney contributed to the study. Results appear online in the Proceedings of the National Academy of Sciences.

The work reported in these two papers was supported by awards from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, U.S. Agency for International Development (PREDICT), the Centers for Disease Control, and the Department of Defense.

April 22, 2012

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