Medco's Specialty Pharmacy Improves Hepatitis C Patient Outcomes, Drives Down Costs by an Average $13,000 Per Patient

Accredo Health Group poised to aid patients with new treatments

HCV patient compliance remains high for complex medication regimen

FRANKLIN LAKES, N.J., July 5, 2011 /PRNewswire/ -- Accredo Health Group Inc., the specialty pharmacy of Medco Health Solutions, Inc. (NYSE: MHS), has developed a unique ability to manage the costs of treating hepatitis C (HCV), while keeping patients adherent to a complex medication regimen for a sometimes lethal disease that can lead to liver cirrhosis and certain cancers. The introduction of two new HCV medications that hold tremendous promise but also add even a greater degree of complexity to treatment will require this "high touch" approach to help increase patient adherence.

Patients must be at least 80-85 percent adherent to therapy for the HCV treatment to be effective, and Accredo has results demonstrating that patients who receive therapy from Accredo's nurses and specialist pharmacists are nearly 10 percent more adherent than those who get their therapy from another provider. Accredo has also been successful in using genotype information to identify patients who may need only 24 weeks of therapy, resulting in drug cost savings up to $13,000.

Accredo's high-touch care model helps educate patients about their treatment and the necessity to adhere to it. This includes patient instruction about using their medications, communicating with doctors about treatment programs and assisting patients to manage side effects. This, in turn, helps to improve patient outcomes and reduce costly hospitalizations or the wastage of expensive medications that are not being properly taken.

As Accredo has improved care for HCV patients, boceprevir and teleprevir will likely improve patients' odds for beating the condition that affects 3.2 million Americans, sparing thousands of patients from liver failure, potential transplants or cancer.

"These new drugs will likely be game-changers for HCV patients, but patients are going to need help adhering to treatment," said Richard Faris, vice president and national practice leader for Medco's Rare and SpecialtyTherapeuticsResourceCenter. "Medco's enhanced clinical oversight and expertise in gene-based medicine enables us to help patients get the right treatment and stay on therapy."

The U.S. Food and Drug Administration (FDA) approved the medications in May to supplement treatments of pegylated interferon and ribavirin in patients with HCV genotype 1, the most common type of the virus. The new treatments improve efficacy to approximately 75 percent from 50 percent when pegylated interferon and ribavirin, the standard of care for HCV since 2001, are used together for 48 weeks. At the same time, the new drugs can shorten the duration of treatment to 24 weeks in most patients. Despite being oral drugs, the new treatments that prevent HCV from replicating add a layer of complexity to an already complex treatment program.

The Accredo Model

The Hepatitis C Therapeutic Resource Center at Accredo has been successful in helping patients, physicians and payers with this difficult therapeutic regimen. Accredo's approach is to maximize clinical effectiveness for patients and benefits plan sponsors by reducing the potential for waste. Failure to properly monitor the therapy, genotype and viral load can cost up to $64,000 in unnecessary drug costs for treating an HCV patient. Pegylated interferons are dosed in precise increments based on a patient's weight.

Patient adherence to these therapies is crucial to achieving a successful course of therapy, but made difficult given their significant side effects and intensive drug regimen. Accredo's Hepatitis C Therapeutic Resource Center services include patient training, preventing drug waste, coordination of care, genetic screening, and patient monitoring and counseling to overcome barriers to treatment adherence.

Hepatitis C and its costs

HCV – and subsequent liver cirrhosis – is the leading cause of liver transplant and it is estimated that 30 percent of the 17,000 people on the liver transplant list are infected with HCV. The initial cost for a liver transplant is $315,000 with follow-up care costing $22,000 annually. HCV is also a leading cause of liver cancer. HCV patients also can have significant co-morbidities that require complex care from specialty pharmacy. For example, in the United States up to 8 percent of those with chronic HCV may be HIV co-infected. Overall, an estimated 6,200 persons with bleeding disorders are affected by HCV, representing 44 percent of all persons with hemophilia and 5 percent of all persons with von Willebrand disease. Persons above the age of 21 have the highest rates of infection, since they were most likely to get human blood products as treatment.

About Medco

Medco Health Solutions, Inc. (NYSE: MHS) is pioneering the world's most advanced pharmacy® and its clinical research and innovations are part of Medco making medicine smarter™ for more than 65 million members.

With more than 24,000 employees worldwide dedicated to improving patient health and reducing costs for a wide range of public and private sector clients, and 2010 revenues of $66 billion, Medco ranks 34th on the 2011 Fortune 500 list and is named among the world's most innovative, most admired and most trustworthy companies. Accredo Health Group, Inc., is a wholly-owned subsidiary of Medco.

For more information, go to http://www.medcohealth.com/.

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties that may cause results to differ materially from those set forth in the statements. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. We undertake no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Forward-looking statements are not historical facts, but rather are based on current expectations, estimates, assumptions and projections about the business and future financial results of the pharmacy benefit management ("PBM") and specialty pharmacy industries, and other legal, regulatory and economic developments.

SOURCE Medco Health Solutions, Inc.

RELATED LINKS
http://www.medcohealth.com/

Source

Hepatitis delta virus

The Lancet, Volume 378, Issue 9785, Pages 73 - 85, 2 July 2011

doi:10.1016/S0140-6736(10)61931-9
Published Online: 20 April 2011

Sarah A Hughes MBBCh a, Heiner Wedemeyer MD c, Dr Phillip M Harrison MD b

Summary

Hepatitis delta virus (HDV) is a small, defective RNA virus that can infect only individuals who have hepatitis B virus (HBV); worldwide more than 15 million people are co-infected. There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity. The hepatitis D virion is composed of a coat of HBV envelope proteins surrounding the nucleocapsid, which consists of a single-stranded, circular RNA genome complexed with delta antigen, the viral protein. HDV is clinically important because although it suppresses HBV replication, it causes severe liver disease with rapid progression to cirrhosis and hepatic decompensation. The range of clinical presentation is wide, varying from mild disease to fulminant liver failure. The prevalence of HDV is declining in some endemic areas but increasing in northern and central Europe because of immigration. Treatment of HDV is with pegylated interferon alfa; however, response rates are poor. Increased understanding of the molecular virology of HDV will identify novel therapeutic targets for this most severe form of chronic viral hepatitis.
 
Source

Interleukin-28B genetic variants in identification of hepatitis C virus genotype 1 patients responding to 24 weeks peginterferon/ribavirin

J Hepatol. 2011 May 19. [Epub ahead of print]

Huang CF, Huang JF, Yang JF, Hsieh MY, Lin ZY, Chen SC, Wang LY, Juo SH, Chen KC, Chuang WL, Kuo HT, Dai CY, Yu ML.

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Abstract

BACKGROUND: A substantial proportion of hepatitis C virus genotype 1 (HCV-1) patients achieved a sustained virological response (SVR, HCV RNA seronegative throughout 24 weeks of post-treatment follow-up) after 24 weeks peginterferon/ribavirin therapy. We explored the role of interleukin-28B genotype in identifying patients who responded to the regimen.

METHODS: Interleukin-28B rs8099917 genotype was determined in 226 HCV-1 patients with 24 weeks peginterferon/ribavirin.

RESULTS: Comparing to patients with rs8099917 TG/GG genotype, those with TT genotype had significantly higher rapid virological response (RVR, HCV RNA seronegative at treatment week 4, 54.0% vs. 17.9%, P<0.001) and SVR (64.7% vs. 25.6%, P<0.001) rates, and lower relapse rate (28.0% vs. 54.5%, P=0.01). Logistic regression analysis revealed that the strongest factor predictive of a RVR was the carriage of rs8099917 TT genotype (odds ratio/ 95% confidence intervals [OR/CI]: 6.24/2.34-16.63), followed by lower viral loads (OR/CI: 5.29/2.81-9.93) and age (OR/CI:0.94/0.91-9.97). The most important factor predictive of an SVR was the attainment of a RVR (OR/CI: 22.23/9.22-53.58), followed by the carriage of rs8099917 TT genotype (OR/CI: 3.38/1.18-9.65), lower viral loads (OR/CI: 2.23/1.00-4.93) and ribavirin exposure dose (OR/CI: 1.17/1.06-1.30). The determinant power of rs8099917 genotype on SVR was mainly restricted to non-RVR patients, particularly those with higher baseline viral loads. Combination of the two pretreatment predictors, interleukin-28B genotype and baseline viral loads, could predict treatment efficacy with a positive predictive value of 80% and a negative predictive value of 91%.

CONCLUSIONS: Interleukin-28B genotype could help identifying patients who are or are not candidates for an abbreviated regimen before treatment.

Copyright © 2011. Published by Elsevier B.V.

Source

Oral combination therapy: Future hepatitis C virus treatment?

J Hepatol. 2011 May 19. [Epub ahead of print]

Hézode C.

Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France.

Abstract

COMMENTARY ON:: Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): A randomised, double-blind, placebo-controlled, dose-escalation trial. Gane EJ, Roberts SK, Stedman CA, Angus PW, Ritchie B, Elston R, Ipe D, Morcos PN, Baher L, Najera I, Chu T, Lopatin U, Berrey MM, Bradford W, Laughlin M, Shulman NS, Smith PF. Lancet 2010 Oct 30;376(9751):1467-75. Reprinted from The Lancet, Copyright (2010), with permission from Elsevier. http://www.ncbi.nlm.nih.gov/pubmed/20951424

BACKGROUND: Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs-RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor-in patients with chronic HCV infection.

METHODS: Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13days oral combination treatment with RG7128 (500 or 1000mg twice daily) and danoprevir (100 or 200mg every 8h or 600 or 900mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo. Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment-experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment allocation. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov., NCT00801255.

FINDINGS: Eighty-eight patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose). The median change in HCV RNA concentration from baseline to day 14 ranged from -3.7 to -5.2 log(10)IU/ml in the cohorts that received 13days of combination treatment. At the highest combination doses tested (1000mg RG7128 and 900mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was -5.1 log(10)IU/ml (IQR-5.6 to -4.7) in treatment-naive patients and -4.9 log(10)IU/ml in previous standard of care null responders (-5.2 to -4.5) compared with an increase of 0.1 log(10)IU/ml in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontinuations.

INTERPRETATION: This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV.

Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Source

Therapeutics: New drugs hit the target

Jana Schlütter

Nature 474,S5–S7(09 June 2011) doi:10.1038/474S5a Published online 08 June 2011

With two recently approved drugs and dozens more in the pipeline, hepatitis C treatment will improve over the next decade.

When Charles Gore talks about some of his colleagues, there is more than a hint of urgency in his voice. Although he cleared his hepatitis C virus (HCV) infection after receiving the standard treatment, two of his staff at the World Hepatitis Alliance, an advocacy organization, recently had liver transplants. “And they are lucky,” says Gore, who is president of the alliance. “This treatment does not help about 50% of the patients who are infected with the most common form of the virus. So their liver becomes worse, and many of them cannot get a transplant. They are facing death.”

Around the globe, patients who have not been cured by the current treatment, a combination of interferon-α and ribavirin, are waiting for new drugs. So far, their doctors have had nothing to offer them but another 48-week-round of the same drug combination, which had its last upgrade in 2001 when researchers attached a molecule called polyethylene glycol to interferon-α. This 'pegylation' allows interferon-α to stay in the body much longer, reducing the frequency of injections from three per week to one. But the side effects are just as harsh, including flu-like symptoms, anaemia and depression. And although the patient being treated may be too weak to work or enjoy family life, the virus often manages to survive and prosper under these conditions. At most, 20% of patients are cured by this second course of treatment. Still, there was no alternative.

This situation is about to change. Two powerful weapons against chronic HCV infection have been licensed: the protease inhibitors telaprevir, from Vertex Pharmaceuticals, based in Cambridge, Massachusetts, and boceprevir, from drug company Merck, headquartered in Whitehouse Station, New Jersey. When either drug is added to the current therapy, the cure rate increases for patients who have so far been spared the daunting year-long treatment: that is, 'treatment-naive' patients. The drugs also offer hope to those increasingly desperate patients who have not been helped by the standard treatment: instead of around a 20% chance of a cure, these 'treatment-experienced' patients now have a 30–90% chance. “We are approaching a new era of management of this disease,” says Mark Thursz, a hepatologist at Imperial College London and current secretary-general of the European Association for the Study of the Liver (EASL).

The drug manufacturers have tailored these protease inhibitors to HCV genotype 1, one of at least six forms of HCV. Genotype 1 is particularly widespread in the United States and Europe and is one of the least responsive to the standard treatment. The clinical studies coming out now, Thursz says, “show that the new drugs can tame the pit bull terriers of the hepatitis C world: the genotype 1 viruses.”

In addition to telaprevir and boceprevir, there are dozens of compounds in the pipeline, and that's only counting the ones that drug manufacturers are willing to disclose. These drugs target many aspects of the virus's life cycle — the stages it goes through in the liver cell to reproduce itself. Used in combination, the new agents might be able to target all HCV genotypes at once, while improving the cure rate and preventing drug resistance from emerging. Although most of these drug candidates are being added to the current treatment, an interferon-free regimen has recently shown promise — a possibility that could substantially reduce treatment side effects and increase adherence.

Direct hits

In the current regimen, interferon-α boosts the patient's immune system, and ribavirin is a general inhibitor of virus replication. By contrast, the new drugs target HCV directly. Telaprevir and boceprevir block HCV's NS3/4A protease. After an HCV particle attaches to and enters a liver cell, it releases its RNA, which is subsequently translated into a single polyprotein (see 'The life of HCV'). This long chain is cleaved into functional proteins by NS3/4A, which acts like a pair of molecular scissors. Without the protease, functional viral enzymes and structural proteins are not generated, so HCV cannot complete its life cycle.

SOURCE: CIESEK, S. & MANNS, M. P. NAT. REV. GASTROENTEROL. HEPATOL. 8, 69–71 (2011).

This March, the drug companies reported results of phase III clinical trials of telaprevir and boceprevir, each coupled with the current therapy, at EASL's International Liver Congress in Berlin. Two-thirds to three-quarters of treatment-naive patients with HCV genotype 1 are likely to clear the virus permanently. And treatment time is expected to be halved for patients in this group who have undetectable levels of virus after four weeks of treatment.

More hotly anticipated were the data for the treatment-experienced patients, including relapsers, whose virus had become undetectable but rebounded after their previous treatment ended; partial responders, whose viral load decreased by at least 99% but never became undetectable; and null responders, who previously had little success in fighting the virus. Telaprevir was tested in the Realize trial, which involved 662 patients from Europe and the United States. Adding telaprevir for 12 weeks to a 48-week-treatment course increased the cure rates from 24% to as high as 88% in relapsers, from 15% to 59% in partial responders, and from 5% to 33% in null responders. Boceprevir was tested in 403 patients in centres across the United States and Europe in the Respond-2 trial. Adding boceprevir for 32–44 weeks caused the cure rate to climb from 29% to 69-75% in relapsers and from 7% to 40-52% in partial responders. (Null-responders did not participate in this trial.)

“To have direct-acting antivirals against hepatitis C and to see such increases in cure rates is a huge step forward,” says Stefan Zeuzem, a hepatologist at the Goethe University Medical Center in Frankfurt, Germany, who was involved in both the Realize and Respond-2 trials. But these drugs are not cheap. “Cost will be a major issue,” he says. “However, we are preventing liver cancer and other end-stage liver diseases, which makes it worthwhile. We are aiming for a cure, not just a few more weeks to live.”

Both of these drugs also have side effects. More than half of the patients treated with telaprevir developed a rash, with 3–6% having a rash severe enough to halt treatment. Boceprevir is associated with anaemia (similarly to telaprevir) and can cause a metallic taste in the mouth, both of which affect nearly half of all patients. These problems are in addition to those caused by interferon-α and ribavirin, meaning that nearly every patient in the clinical trials suffered from at least one side effect. “It's still a tough treatment,” says Gore. “For patients, it's very important that clinicians manage these side effects well.”

If side effects cause patients to abandon treatment on the new regimen, this could lead to HCV developing resistance to the new drugs. The new protease inhibitors cannot be given alone and must be given with interferon-α and ribavirin to prevent protease-inhibitor resistance emerging. Thursz adds that as boceprevir and telaprevir are similar compounds, resistance to one will probably translate into resistance to the other (so-called cross-resistance), restricting future treatment options.

HCV is a highly mutation-prone virus, with many genetic variants present in any one host. Before treatment starts, variants that are resistant to a particular drug make up a minority of the viral population. Under selective pressure of the antivirals, however, these variants could become the dominant strains. “We understand resistance and have to manage it,” says Jean-Michel Pawlotsky, a hepatitis specialist at the University of East Paris in Créteil, France, and director of the French National Reference Center for Viral Hepatitis B, C and delta. He recommends that these new drugs should be administered at expert centres that can monitor resistance issues: “It is better to be well-treated than just treated,” he says.

Despite the high cure rates, not every HCV-infected patient will benefit from the new drugs. Possible drug–drug interactions are not yet fully understood. And there are no data for the many patients who are co-infected with HIV or for patients with end-stage renal disease, decompensated (or extremely advanced) liver cirrhosis or a recent liver transplant. Furthermore, telaprevir and boceprevir have been licensed by the US Food and Drug Administration only for treating HCV genotype 1 infection. As Pawlotsky says, “What we are seeing now is just the first step into the era of direct-acting antivirals. It will cause a real shift, but it's not a full revolution.”

Covering every angle

More than 50 other drugs are, however, in the research and development pipeline (see 'Drug candidates for treating HCV infection 2011'). Many of these are in new classes — that is, they target different mechanisms — and can be combined to create antiviral cocktails, limiting the emergence of drug resistance. With so many new agents snapping at their heels, boceprevir and telaprevir might have a very limited time as the dominant new drugs, says Zeuzem.

Two other first-generation protease inhibitors are in phase III trials: TMC435, from Tibotec Pharmaceuticals, in Beerse, Belgium, and pharmaceutical company Medivir in Huddinge, Sweden; and BI201335, from pharmaceutical company Boehringer Ingelheim, headquartered in Ingelheim am Rhein, Germany. Both are taken once daily instead of three times, seem to cause fewer side effects and might even be more potent than boceprevir and telaprevir.

The second generation of protease inhibitors is expected to be led by Merck's MK-5172, a compound that does not seem to have cross-resistance issues with other drugs of this class and might be effective across multiple genotypes. “We want to see if the resistance profile is robust enough that we can treat people who are failures from earlier generations of protease inhibitors,” says Keith Gottesdiener, vice president for hepatitis C clinical development at Merck. “That would be exciting if it was proven in the clinic.”

The pharmaceutical company F. Hoffmann-La Roche, headquartered in Basel, is about to start phase III trials of mericitabine, which blocks the activity of HCV's polymerase enzyme, NS5B. By mimicking the building blocks of RNA, mericitabine is incorporated into newly formed viral RNA but prematurely terminates it, halting the life cycle.

Another protein generating immense interest as a drug target is NS5A. Its precise function is mysterious, but it seems to be involved in the replication, assembly and release of HCV. BMS-790052, from biopharmaceutical company Bristol-Myers Squibb, headquartered in New York, was the first inhibitor in this class and is now in phase II trials. The pipeline is rapidly filling with others.

Cyclophilin A inhibitors block a host protein that is essential for viral replication. Candidates include alisporivir (DEB025), from drug company Novartis, headquartered in Basel, Switzerland, which is in phase III trials. In theory, targeting a human protein that HCV needs will render the virus' genotype or mutation status irrelevant and make it much less likely that resistant strains of HCV will emerge.

Free from interferon

There is also hope for patients who are not responsive to — or cannot tolerate — the backbone of triple therapy: interferon. This April at the International Liver Congress, Anna Lok, a hepatologist at the University of Michigan in Ann Arbor, presented data from a small phase IIa study of an interferon-free regimen in null responders. The study comprised patients on double therapy consisting of two classes of direct-acting antiviral: Bristol-Myers Squibb's BMS-650032 (a protease inhibitor) and BMS-790052 (an NS5A inhibitor). These patients were compared with a cohort taking quadruple therapy, consisting of these two antivirals plus interferon-α and ribavirin. The quadruple therapy suppressed HCV in 10 out of 10 patients for at least 12 weeks after treatment, whereas the interferon-free double therapy suppressed HCV in 4 out of 11 patients, with 6 being null or partial responders.

The numbers might not seem great, but they are a start. “The potential for an interferon-free regimen is some of the most exciting news this year,” says Thursz. Without interferon-α and ribavirin, the virus was expected to rebound after treatment, but this occurred in only one case. “There is still a lot of work to be done. But this was a group of very difficult-to-treat patients with excellent outcomes. Although the numbers are small, I think this is the direction we can expect to go in the future.”

Indeed, this possibility has energized hepatitis C researchers. “People would have laughed at you if you suggested something like this five years ago,” says Zeuzem. “Now, we know that such a therapy might be available in another five to ten years.”

Many of the other drugs in the pipeline, such as the NS5B inhibitors, could also be candidates for an interferon-free regimen, says Paul Pockros, co-director of clinical research at the Scripps Translational Science Institute in La Jolla, California, who is involved in phase II studies of mericitabine. Although mericitabine is slightly less effective than the protease inhibitors, it seems to be a safe drug with a high barrier to resistance. “This one would be a good partner for a protease inhibitor,” says Pockros.

With all the excitement about new drugs, one would be forgiven for thinking that interferon has had its day. But there is also development on this front. Bristol-Myers Squibb has developed a variant called pegylated interferon-λ, which is designed to be more potent and safer than interferon-α. Interferon-λ docks with different receptors that are less common than the receptors for interferon-α. This interferon circumvents the bone marrow and therefore avoids anaemia and flu-like symptoms, so it might be a good partner for direct-acting antivirals. “This would help a lot of people who cannot tolerate the current interferon,” says Zeuzem, who is involved in clinical trials of this drug.

With interferon-free regimens on the horizon, the question is whether a new interferon will be needed. But there are many potential pitfalls on the way to the clinic, and HCV is a very difficult virus to target. Researchers need as many options at their disposal as possible, says Zeuzem, “just in case.”

Source

Needle-Exchange Programs Limit Spread of Hepatitis C

By Amy Norton

NEW YORK (Reuters Health) Jun 29 - Programs that give drug users clean needles or safer drug substitutes can cut the spread of hepatitis C, a new study suggests.

In the U.S., most of the roughly 18,000 new infections each year occur when drug users share tainted needles or syringes. Studies have found that clean-needle programs reduce needle-sharing and seem to protect against infection with HIV. The same appears true of programs that get addicts into treatment with methadone.

There has been little evidence that these programs help cut the spread of hepatitis C. But the new findings, published online May 25th in Addiction, suggest that needle and opiate-substitution programs can make a difference in hepatitis C risk, according to senior researcher Matthew Hickman at the University of Bristol in the UK.

Combining the results from six previous studies of UK programs, Hickman's team found that drug users with the highest "coverage" from clean-needle programs were about half as likely to acquire HCV infection as other users.

Among users who said they got enough clean needles to cover all of their injections, just under 4% became HCV-positive. That compared with 7% of drug users who didn't get clean needles for all their injections.

Similarly, the rate of new hepatitis C infection was 3% among drug users who were currently taking an opiate substitute (usually oral methadone), versus 7% among those not on treatment.

Drug users participating in both types of programs fared best of all, with a new infection rate of 2%.

"The implication is that hepatitis C transmission can be reduced by opiate substitution therapy and needle and syringe programs, especially their combination," Hickman told Reuters Health in an email.

While the study looked only at UK programs, it's likely the results would be similar in other countries, he said.

The study has its limits. Its findings are based on observational studies and small numbers. The researchers had usable information on 919 program participants across the six study sites, and there were 40 cases of new hepatitis C infection.

Still, Hickman said the study starts to fill a gap in the knowledge of how well injection drug use programs are working.

SOURCE: http://bit.ly/lMvRUW

Addiction 2011.

Source
 
Also See: Programs may curb hepatitis C in drug users

Living donor liver transplantation from a donor previously treated with interferon for hepatitis C virus: a case report

Published on: 2011-07-03

Introduction: Selecting a marginal donor in liver transplantation (LT) remains controversial but is necessary because of the small number of available donors.Case presentationA 46-year-old Japanese woman was a candidate to donate her liver to her brother, who had decompensated liver cirrhosis of unknown origin. Eight years before the donation, she had a mild liver dysfunction that was diagnosed as a hepatitis C virus (HCV) infection (serotype 2).

She had received anti-viral therapy with interferon -2b three times weekly for 24 weeks and had a sustained viral response (SVR). A biopsy of her liver before the donation showed normal findings without any active hepatitis, and her serum was negative for HCV-RNA.

Only 67 patients have undergone LT from a cadaveric donor in Japan. The family in this case decided to have living donor LT.

A careful selection for the liver graft donation was made; however, since she was the only candidate, we approved her as a living donor. She was discharged nine days after the liver donation.

Her liver function recovered immediately. A computed tomography scan showed sufficient liver regeneration one year later.

Her brother also had good liver function after LT and had no HCV infection 48 months after surgery and no de novo malignancy. Neither of the siblings has developed an HCV infection.

Conclusions: A patient with SVR status after interferon therapy might be considered a candidate for living donor LT but only if there are no other possibilities of LT for the recipient.

A careful follow-up of the donor after donation is needed. The recipient also must have a very close follow-up because it is difficult to predict what might happen to the graft with post-transplant immunosuppression.

Author: Masaaki HidakaMitsuhisa TakatsukiAkihiko SoyamaHisamitsu MiyaakiTatsuki IchikawaKazuhiko NakaoTakashi KanematsuSusumu Eguchi

Credits/Source: Journal of Medical Case Reports 2011, 5:276

Source

Genetic Variant Linked to Development of Liver Cancer in Hepatitis C Virus Carriers

Tokyo, July 4, 2011 - (JCN Newswire) - A genome-wide study by researchers at the RIKEN Center for Genomic Medicine, Hiroshima University Hospital and Sapporo-Kosei General Hospital has identified a genetic variant associated with the development of liver cancer in chronic hepatitis C virus carriers. The findings are based on a study of 3,312 Japanese individuals and appear in the journal Nature Genetics.

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the third leading cancer-related cause of death and the seventh most common form of cancer worldwide. The hepatitis C virus (HVC) is the main risk factor for HCC in many western countries and in Japan, where of the more than 30,000 deaths each year from HCC, 70% involve HVC.

To identify risk factors connecting HVC and HCC, the research group conducted a genome-wide study on a group of 3,312 Japanese individuals carrying the hepatitis C virus. Analyzing a total of 467,538 genetic markers (called single nucleotide polymorphisms or SNPs) in a group of 212 HCV carriers with HCC and 765 HCV carriers without HCC, the group uncovered one SNP associated with HCC risk, located on a gene called DEPDC5. The association was confirmed in an independent replication study on a population of 2335 HVC carriers, 710 with HCC and 1625 without HCC.

The significance of the findings was further highlighted when the researchers adjusted their results for gender, age and platelet count, revealing that among Japanese individuals with chronic HVC infection, the DEPDC5 SNP roughly doubles the odds of developing HCC.

While deepening our understanding of the mechanisms triggering HCC, the discovery of the DEPDC5 SNP locus also provides a valuable target for new therapy techniques, promising progress in the ongoing battle to overcome one of the world's most deadly cancers.

Reference:

Daiki Miki, Hidenori Ochi, C Nelson Hayes, Hiromi Abe, Tadahiko Yoshima, Hiroshi Aikata, Kenji Ikeda, Hiromitsu Kumada, Joji Toyota, Takashi Morizono, Tatsuhiko Tsunoda, Michiaki Kubo, Yusuke Nakamura, Naoyuki Kamatani & Kazuaki Chayama. Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nature Genetics, doi:10.1038/ng.876.

About RIKEN Institute

RIKEN, one of Japan's leading research institutes, conducts basic and applied experimental research in a wide range of science and technology fields including physics, chemistry, medical science, biology and engineering. Initially established as a private research foundation in Tokyo in 1917, RIKEN became an independent administrative institution in 2003. For more information, visit www.riken.jp/engn/index.html.

Contact:

Kazuaki Chayama
Laboratory for Digestive Diseases
RIKEN Center for Genomic Medicine (CGM),
Tel: +81-82-257-5955
Fax: +81-82-257-1559

Ms. Tomoko Ikawa (PI officer)
Global Relations Office
RIKEN
Tel: +81-48-462-1225
Fax: +81-48-463-3687
Email: koho@riken.jp

Source

Telaprevir Markedly Improves HCV Genotype 1 Cure Rates

Summary and Comment

Final results of phase III trials show that telaprevir plus standard therapy with peginterferon alfa-2a and ribavirin was more effective than standard therapy alone.

Recently, telaprevir-based triple therapy (i.e., in combination with peginterferon alfa-2a and ribavirin) was approved for the treatment of chronic hepatitis C virus (HCV) infection. The final results of the international phase III trials for both treatment-naive and treatment-experienced patients with HCV genotype 1 infection are now available.

In the first of two industry-sponsored, double-blind, placebo-controlled trials, 1095 treatment-naive patients were randomized to receive either triple therapy for 12 weeks followed by peginterferon plus ribavirin for 12 weeks — or 36 weeks if HCV RNA was detectable at weeks 4 or 12 — (T12PR group); triple therapy for 8 weeks followed by peginterferon plus ribavirin for either 16 or 36 weeks (T8PR group); or peginterferon plus ribavirin for 48 weeks (PR group).

In the second trial, 663 treatment-experienced patients were randomized 2:2:1 to receive either triple therapy for the first 12 weeks followed by 36 weeks of peginterferon plus ribavirin (T12PR48 group), a 4-week lead-in of peginterferon plus ribavirin followed by 12 weeks of triple therapy and then 32 weeks of peginterferon plus ribavirin (lead-in T12PR48 group), or peginterferon plus ribavirin for 48 weeks (PR48 group). In both trials, doses were 750 mg every 8 hours for telaprevir, 180 µg weekly for peginterferon alfa-2a, and 1000–1200 mg daily for ribavirin. The primary endpoint was sustained virologic response (SVR).

For treatment-naive patients, SVR rates were higher in the T12PR and T8PR groups than in the PR group — 75% and 69% versus 44%; P<0.001. Although the numbers of patients who were black or had advanced fibrosis were small in the study cohort (7% and 20%, respectively), in both subgroups, SVR rates were higher in the telaprevir groups than the peginterferon plus ribavirin group.

Among treatment-experienced patients, SVR rates for arms T12PR48, lead-in T12PR48, and PR48, respectively, were 83%, 88%, and 24% for previous relapse; 59%, 54%, and 15% for previous partial response; and 29%, 33%, and 5% for previous null response (P<0.001 for all comparisons). In general, virologic failure in the telaprevir groups was attributable primarily to the development of drug resistance. In both studies, the telaprevir groups had higher rates of anemia, rashes, pruritus, and gastrointestinal problems than the peginterferon plus ribavirin group. Discontinuation of medications for any reason ranged from 10% to 15% for the telaprevir regimens and from 7% to 10% for the peginterferon plus ribavirin regimen.

Comment: These companion studies demonstrate that telaprevir-based regimens are significantly more effective in HCV genotype 1–infected patients than peginterferon plus ribavirin alone — for both treatment-naive and treatment-experienced patients. Although more adverse events occurred in the telaprevir-treated groups, discontinuation rates were still relatively low. Overall, the best SVRs were seen in treatment-naive and prior-relapse patients (75%), followed by previous partial responders, treatment-naive blacks, and patients with advanced fibrosis (50%–60%), and last, previous null responders (30%). Therefore, caution should be exercised in treating null responders, especially since the majority of virologic failure leads to drug resistance.

— Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology July 1, 2011

Citation(s):

Jacobson IM et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011 Jun 23; 364:2405.
Medline abstract (Free)

Zeuzem S et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011 Jun 23; 364:2417.
Medline abstract (Free)

Innovative vaccines with nanotechnology

Public release date: 1-Jul-2011

Contact: Dr. Bastian Dornbach
bastian.dornbach@helmholtz-hzi.de
49-531-618-11407
Helmholtz Association of German Research Centres

European Research Consortium wants to develop novel vaccination against hepatitis C

HCVAX is a European joint project that reaches out to develop a vaccine against hepatitis C based on nanotechnology. The German Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI) in Braunschweig and its department "Vaccinology and Applied Microbiology" is now a part of the transnational consortium with researchers from Germany, France and Switzerland.

More than 170 million people are infected with the hepatitis C virus (HCV) worldwide. Also in Europe this form of hepatitis is a big problem with three per cent of the population affected. The virus is transmitted in operations such as transplantations or by the re-use of syringes for drug usage. Anti-viral treatments are very expensive, have serious side effects and are only effective for some patients. Most of the patients carry the infection for the rest of their lives, with the threat of later developing liver cirrhosis and cancer. Certainly, the most effective way to combat hepatitis C would be a vaccine against the virus – but to date no efficacious vaccine exists.

"We will pursue a completely new approach to develop a HCV vaccine," says Prof. Carlos A. Guzmán, head of the Vaccinology Department at the HZI. With the help of innovative, biocompatible nanogels part of the genetic information of the virus is brought into the body by so-called "RNA replicons". The synthetic nanogels have a diameter of only a few nanometres and are composed of a biopolymer matrix. Immune cells will take up the nanogels with the genetic information and will produce harmless components of HCV. The immune cell then responds to those foreign structures and will generate memory cells: with this, the vaccination would be successful and from then on one would be protected against an infection with pathogen HCV.

By using novel drug amplifiers, so-called adjuvants, the immune response shall be more efficient and targeted. "The HZI has a long-standing expertise in this field. We will incorporate this knowledge into the project to develop more effective vaccines," says Guzmán. "We want to identify those adjuvants that are most eligible for a use in the nanogel composition. The targeted transport to certain defence cells shall guarantee an optimal immune response."

To exclude side effects, potential vaccine candidates have to be tested in several systems. Promising structures will then be selected for further clinical development.

The consortium consists of two companies, three academic institutions and one clinic. They combine their expertise on the field of nanotechnology, biochemistry, immunology, vaccine development and clinical research. "Beyond that we expect that these novel vaccination strategies can be expanded onto the clinical management of other diseases," says Guzmán.

Funding is granted for the next three years from the "EuroNanoMed Joint Transnational Initiative" of the European Union. The German Ministry for Research and Education is funding the project in Germany.

The Partners:
Federal Department of Economic Affairs (Eidgenössisches Volkswirtschaftsdepartement), Mittelhäusern, Switzerland (coordinator)
Medipol SA, Lausanne, Switzerland
Institut Pasteur, Paris, France
Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung GmbH), Braunschweig, Germany
EDI GmbH, Reutlingen, Germany
Hôpital Cochin, Paris, France

Source

Responding to the National HIV/AIDS Strategy-setting the Research Agenda

Stephen F. Morin, PhD; Jeffrey A. Kelly, PhD; Edwin D. Charlebois, PhD, MPH; Robert H. Remien, PhD; Mary J. Rotheram-Borus, PhD; Paul D. Cleary, PhD

Posted: 06/30/2011; J Acquir Immune Defic Syndr. 2011;57(3):175-180. © 2011 Lippincott Williams & Wilkins

Abstract and Introduction

Introduction

The National HIV/AIDS Strategy (NHAS) has 3 goals: (1) reduce the number of people who become infected with HIV, (2) increase access to care and improve health outcomes of people living with HIV, and (3) reduce HIV-related health disparities.[1] In addition, the plan and its implementation strategy call for achieving more coordination of HIV programs across the federal government and between federal agencies and state and local governments.[2] Accompanying the strategy is an implementation plan that identifies the steps to be taken by federal agencies and all parts of society to support the priorities outlined in the strategy and sets targets for the 3 goals to be achieved by 2015 (eg, lowering the number of new HIV infections by 25%).[3] We lay out a role for the National Institutes of Health in facilitating research that supports and informs the goals of the NHAS.

Although the potential benefits of the National HIV Strategy for HIV-infected persons and the broader society are substantial, 3 important challenges must be addressed to effectively bring the strategy to scale in the United States. First, although virtually everyone who is HIV infected is eventually identified, diagnosis often occurs too late in the disease to provide optimal benefit to the individual. In addition, until persons know they are infected, they are more likely to transmit their infection to others. Thus, it is critical to detect HIV-infected individuals earlier in their disease. Second, once HIV-infected individuals are identified, it is crucial that they quickly receive and then remain in care. Third, if the individual and society are to benefit from antiretroviral therapy, infected persons must receive and be adherent to treatment to maintain long-term virologic suppression to achieve better health outcomes and reduce HIV transmission rates.

Although an emphasis on testing and treatment sounds primarily biomedical, the 3 challenges depend on behavioral, social, system, and structural factors important to address in the implementation of the NHAS. Early identification of HIV infection, especially for populations with greatest disease incidence, requires community-level and provider-level interventions to make frequent HIV testing normative, easy to obtain, and free of stigma. Engaging and maintaining HIV-infected persons in care requires the development and implementation of practical interventions—at health care system, community, and individual levels—targeted toward those marginalized patient groups least likely to enter and remain without disruption in care. Well-maintained HIV virologic suppression, a cornerstone of treatment as prevention approaches, can be achieved only when patients likely to be nonadherent are identified and receive behavioral and social interventions to improve their long-term medication adherence.

Much is known about individual interventions that can achieve some of these goals, but we know much less about how to combine multiple approaches to have the greatest impact on a wide scale. Consensus among researchers is emerging on the need for "combination prevention," by which we mean multilevel interventions that combine evidence-based individual social, behavioral, and biomedical approaches to produce a community-level impact on the HIV/AIDS epidemic.[4,5] It is time to move beyond studying social, behavioral, and biomedical HIV prevention interventions in isolation and instead evaluate the impact of comprehensive, integrated, multilevel approaches implemented on a wide scale.

In this editorial, we will describe some present barriers to implementation of the NHAS, present strategies to address them, and outline research needs relevant to the successful implementation of the strategy.

Improving the Identification of Undiagnosed HIV Infection

The strategy has set as a target to increase the percentage of individuals who are aware of their HIV infection from 79% to 90% by 2015.[3] To accomplish this target, social marketing campaigns designed to make knowledge of one's HIV status normative, such as Washington, DC's "Ask for the Test" campaign[6] and New York City's "Bronx Knows" campaign,[7] have shown promise in decreasing the number of individuals unaware of their HIV infection. Research shows that community mobilization approaches have the potential to reach subpopulations at highest risk for HIV.[8] In addition, the Centers for Disease Control and Prevention (CDC) has recommended routine HIV testing in emergency departments, sexually transmitted disease clinics, and other publicly funded settings for all patients where the patient population has an estimated HIV prevalence of 0.1% or greater.[9]

CDC recommendations call for persons at high risk—men who have sex with men (MSM), injection drug users and their sexual partners, sex workers, sexual partners of HIV-positive individuals, and heterosexuals with multiple partners—to be screened at least annually and for all people being treated for tuberculosis or sexually transmitted diseases to receive HIV testing. More intensive routine screening programs are likely to be cost effective only when focused on high-risk populations, such as black MSM who represent 25% of the HIV epidemic, or in high-risk settings.[10,11] However, implementation of routine testing recommendations has proven challenging. In a recent study of 6 southeastern US community health centers that adopted routine point-of-care rapid testing, only 28% of patients were offered HIV tests and fewer than 70% of those offered chose to have an HIV test.[12] Integrating appropriate HIV testing into private health care settings is a crucial element to identify undiagnosed HIV infections, yet very little research has been conducted in this area. Potential strategies for investigation in the private setting include interventions to increase provider HIV awareness and the use of HIV testing prompts within electronic medical record systems (see Table 1).

Identifying Individuals Earlier in Their Infection

In 2008, about one-third (32%) of individuals with an HIV diagnosis reported to CDC received an AIDS diagnosis within 1 year of their initial diagnosis.[13] Present approaches often identify HIV for the first time only late in the patient's HIV disease course.[13] This pattern is especially pronounced among marginalized populations and ethnic minorities and leads to significant HIV health outcome disparities. Identifying individuals earlier in their HIV infection requires encouraging persons at high risk to test frequently. Research is needed to identify effective community mobilization strategies to facilitate frequent HIV testing, make regular testing normative, and decrease stigma associated with HIV and testing, especially for high-risk populations and undertested minorities.

Specific interventions for low-income persons might include text messaging and low-value cash incentives to promote regular HIV testing. Making rapid HIV tests available to consumers in local pharmacies at a low cost is a strategy that could allow persons in high-risk groups to test their HIV status repeatedly over time, potentially increasing the identification of persons earlier in their course of disease. MSM at high risk for HIV increasingly use the Internet to meet new partners. A promising research intervention for these men is establishing the norm to include in personal profiles the date of last HIV testing; site banners that recommend HIV testing every 3 months for those at risk could be employed as well.

A second goal related to early HIV detection is to identify persons very soon after HIV infection, during the acute phase, a period characterized by high risk of HIV transmission to uninfected partners.[14] Identifying acutely HIV-infected persons could be aided by the use of newer HIV testing technologies (eg, fourth-generation enzyme-linked immunosorbent assay testing, combination antibody and antigen testing, or targeted nucleic acid testing of antibody-negative specimens). Research is needed to develop and evaluate acute HIV infection awareness campaigns for the community and providers, emphasizing symptoms that often accompany primary infection and the increased infectiousness of acute HIV infection.[15] Research with a small sample of acutely HIV-infected persons has shown a reduction in transmission risk acts after notification of acute infection status, highlighting the potential to reduce onward HIV transmissions if acutely infected persons are made aware of their status and their increased infectiousness.[16]

Unfortunately, policy does not always translate directly into action. Coordinated public health responses to acute/early HIV infection involving linkage to HIV care and facilitated partner counseling and referral services have been insufficiently studied.[17] A recent Institute of Medicine report identified many of the practical, policy, and regulatory barriers to the implementation of coordinated responses after the diagnosis of acute HIV infection.[18] Researchers must assess the most effective and efficient ways to overcome these barriers.

Linking and Retaining HIV-infected Individuals in Care

The strategy has established a target of increasing the proportion of newly diagnosed individuals who are linked to clinical care within 3 months of their HIV diagnosis from 65% to 85%. In addition to linkage to routine care, it is important to respond to the distinct and separate challenge of retention in care.[19] Differing definitions and methods make measuring linkage to and retention in care difficult; however, we do know that an estimated 30% to 50% of newly diagnosed HIV-infected individuals in the United States fail to establish HIV care within 6 months.[20,21] In addition, missed appointments are reported among 25%-35% of patients with HIV in care,[22–24] and estimates of retention in care (as measured by at least 1 visit every 6 months over a 2-year period) range from 18% to 61%.[25–27]

Engagement in care is vital for the treatment success of individual patients and for prevention at population levels. Care engagement is known to be worse in marginalized populations, resulting in significant health disparities. As with HIV detection and early identification goals, social marketing and community mobilization strategies aimed at making HIV treatment engagement normative need to be researched.

There is precedent for using linkage support services as core elements in medical care, especially for poor ethnic minority patients with cancer,[28] diabetes,[29] and other chronic diseases including HIV.[30] Early research showed the benefits of case management for linking patients with HIV into care.[31,32] More recently, patient navigator interventions have been found to reduce barriers in accessing care and to improve health outcomes for individuals with HIV in the United States.[28–30,33] Navigators, who can be professionals or peers, assist HIV-infected individuals to make use of available resources and develop effective communication with providers, provide practical and emotional support (such as transportation or child care), escort patients, and help them understand the demands of HIV treatment. Patient navigators can be assigned to emergency departments and other health care settings including testing sites to facilitate linkage to care of HIV-infected persons, with the goal of ensuring initial care visits quickly after HIV detection.

Although navigator interventions have shown promise, there is considerable room for improvement in their implementation and in measuring their success. NHAS goals may be better served by defining "linkage success" as receiving an HIV care visit within 1 month of initial HIV diagnosis rather than within 3 months as has been typical in research studies.

Retaining HIV-infected persons in care presents a significant challenge. Missed visits in the first year of care are associated with the risk of death and risk of mortality increases with the number of visits missed.[34] A study of HIV-infected persons in San Francisco showed an almost doubling of mean HIV viral load among those not engaged in care compared with those in care.[35] Given its obvious importance, it is surprising that no randomized controlled trials of interventions to retain HIV-infected persons in care have been conducted; and there is no consistent definition of what is meant by "in care" with respect to frequency or content of visits. In clinical trials testing drugs, cohort retention for study visits is a high priority, yet the strategies used to meet retention targets in trials have not been systematically applied to the challenge of keeping patients with HIV in care. As with linkage to care, patient navigators could be used to track and assist patients—particularly those patients identified as being at high risk for attrition—to stay in care. Research attention to the development and testing of care retention interventions will benefit patients and benefit the field.

Maintaining Viral Suppression and Improving Health Outcomes

Treatment guidelines have gradually shifted toward beginning treatment at higher CD4 cell counts, with the goal of total HIV viral suppression. Recently, many clinicians have concluded that treatment should be recommended for all HIV-infected individuals, regardless of clinical status, at the time of diagnosis to improve long-term health outcomes.[36]

The NHAS aligns well with what the research community has described as a "test-and-treat" approach, which refers to the early identification of HIV and linking and retaining individuals in care with the goal of maintaining viral suppression. The test-and-treat strategy has the potential both to improve the health of HIV-infected individuals and to reduce new infections by reducing HIV-positive individuals' infectivity.[37] In contrast to the virtual eradication of HIV predicted by modeling of test-and-treat approaches in South Africa, modeling of the US epidemic suggests varying reductions in new HIV infections depending on the extent to which treatment and viral suppression are achieved in the community.[38] The goal of the NHAS is a 25% reduction in new infections in 5 years, which is within the range of modeled effects of increased testing and treatment in selected high-prevalence cities in the United States.[35,39–45]

Improvement of health outcomes depends on behavioral factors associated with adherence to both treatment and care. Adherence interventions often involve practical tools such as pillboxes, reminders, and calendars.[46] When warranted, more intensive interventions to improve adherence include cognitive-behavioral approaches, social support, contingency management, home visits, and directly observed therapy.[47–50]

Care for mental health and substance abuse plays a central role in improving health outcomes. Research has shown that substance abuse and depression are prevalent among patients with HIV in care.[51,52] Promising areas of research include short computer-based screening for these conditions and adherence counseling in clinic waiting rooms. Through the use of electronic medical record systems, assessments could be used to generate prompts for clinicians to direct attention to issues of adherence, mental health, and substance use. Clinic-based screening procedures could also include an assessment of HIV transmission risk acts and readiness for behavior change.[53,54] These assessments could lead to provider-based prevention messages tailored to the stages of change model,[55,56] previously shown to be both effective[53] and cost effective for HIV prevention in clinic settings.[57]

Assessing the Impact of Multilevel Interventions

Given the nature of the multilevel interventions needed to implement the NHAS, we must develop and realign our existing research and funding frameworks to evaluate the epidemic impact of these new interventions. Prior HIV/AIDS prevention research has most often examined either theoretically informed individual-level interventions to promote behavior change or biomedical prevention approaches, usually in isolation from one another.[53,54] The synergistic effects of multilevel HIV/AIDS prevention approach, combining both behavioral and biomedical methods, need to be evaluated at the community level.

Indeed, there is progress in this direction with multilevel intervention feasibility research being conducted by the HIV Prevention Trials Network in Bronx, NY, and Washington, DC.[5] In addition, the CDC through its "Enhanced Comprehensive HIV Prevention Planning" program or ECHPP is supporting the implementation of the NHAS in the 12 US cities most affected by the HIV epidemic to assess how multiple interventions can be combined in the most cost-effective and efficient manner in real-world settings.[58–62] National Institutes of Health's researchers are involved in this effort, providing technical assistance to local health departments on evidence-based intervention and community-level evaluation methods.

Recent developments in the use of public health surveillance data give researchers the potential to examine an aggregate biologic measure of HIV-1 viral load for particular geographic locations.[44] Community viral load can serve as a population-level biologic marker of HIV transmission risk and antiretroviral therapy-mediated virologic suppression.[35] This innovation represents a methodological advance for evaluating the success of intervention strategies aimed at achieving goals of the NHAS.

Implementation of multilevel interventions and evaluation of their epidemic impact present challenges to traditional research paradigms. Present methods and research funding emphasize randomized controlled trials of efficacy over evaluation and effectiveness studies responding to implementation challenges, thereby limiting needed research. A possible solution would be for the National Institutes of Health to develop mechanisms focusing on the implementation gaps we have identified. Such an approach could strengthen the evidence base needed to achieve the practical goals outlined in the NHAS. The public health and scientific fields will be well served by the integration of biomedical advances in HIV prevention with the behavioral, social, and structural interventions needed for implementation on a large scale.

References

1.The White House Office of National AIDS Policy. National HIV/AIDS Strategy for the United States. Washington, DC: White House; 2010.

2.The White House Office of National AIDS Policy. National HIV/AIDS Strategy: Federal Implementation Plan. 2010. Available at: http://www.whitehouse.gov/files/documents/nhas-implementation.pdf. The Office of National AIDS Policy (ONAP) is part of the White House Domestic Policy Council. http://www.whitehouse.gov/administration/eop/onap/about. Accessed June 2011.

3.Millett GA, Crowley JS, Koh H, et al. A way forward: the National HIV/AIDS Strategy and reducing HIV incidence in the United States. J Acquir Immune Defic Syndr. 2010;55(suppl 2):S144–S147.

4.Coates TJ, Richter L, Caceres C. Behavioural strategies to reduce HIV transmission: how to make them work better. Lancet. 2008;372:669–684.

5.Vermund SH, Hodder SL, Justman JE, et al. Addressing research priorities for prevention of HIV infection in the United States. Clin Infect Dis. 2010; 50(suppl 3):S149–S155.

6.Castel A, Samala R, Griffin A, et al. Monitoring the impact of expanded HIV testing in the District of Columbia using population-based HIV/AIDS surveillance data. In: Proceedings from the CROI. San Francisco, CA: February 16–19, 2010.

7.Mantsios A, Tsoi B, Futterman D, et al. Preliminary findings from a borough-wide initiative to scale up HIV screening in New York City. In: National HIV Prevention Conference. Atlanta, GA: 2009.

8.Khumalo-Sakutukwa G, Morin SF, Fritz K, et al. Project accept (HPTN 043): a community-based intervention to reduce HIV incidence in populations at risk for HIV in sub-Saharan Africa and Thailand. J Acquir Immune Defic Syndr. 2008;49:422–431.

9.Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55(RR-14):1–17; quiz CE1–4.

10.Patel P, Klausner JD, Bacon OM, et al. Detection of acute HIV infections in high-risk patients in California. J Acquir Immune Defic Syndr. 2006;42:75–79.

11.El-Sadr WM, Mayer KH, Hodder SL. AIDS in America--forgotten but not gone. N Engl J Med. 2010;362:967–970.

12.Myers JJ, Modica C, Dufour MS, et al. Routine rapid HIV screening in six community health centers serving populations at risk. J Gen Intern Med. 2009;24:1269–1274.

13.CDC. Diagnoses of HIV Infection and AIDS in the United States and Dependent Areas, 2008, in HIV Surveillance Report, Volume 20. Atlanta, GA: CDC; 2008.

14.Cohen MS, Pilcher CD. Amplified HIV transmission and new approaches to HIV prevention. J Infect Dis. 2005;191:1391–1393.

15.Remien RH, Higgins JA, Correale J, et al. Lack of understanding of acute HIV infection among newly-infected persons--implications for prevention and public health: The NIMH Multisite Acute HIV Infection Study: II. AIDS Behav. 2009;13:1046–1053.

16.Steward WT, Remien RH, Higgins JA, et al. Behavior change following diagnosis with acute/early HIV infection--a move to serosorting with other HIV-infected individuals. The NIMH Multisite Acute HIV Infection Study: III. AIDS Behav. 2009;13:1054–1060.

17.Kelly JA, Morin SF, Remien RH, et al. Lessons learned about behavioral science and acute/early HIV infection. The NIMH Multisite Acute HIV Infection Study: V. AIDS Behav. 2009;13:1068–1074.

18.Institute of Medicine. HIV Screening and Access to Care. Washington, DC: Institute of Medicine of the National Academies; 2010.

19.Mugavero MJ. Improving engagement in HIV care: what can we do? Top HIV Med. 2008;16:156–161.

20.Fleming PL, Byers RH, Sweeney PA, et al. HIV Prevalence in the United States, 2000. In: 9th Conference on Retroviruses and Opportunistic Infections. Seattle, WA; February 24–28, 2002.

21.Giordano TP, Visnegarwala F, White AC Jr., et al. Patients referred to an urban HIV clinic frequently fail to establish care: factors predicting failure. AIDS Care. 2005;17:773–783.

22.Catz S, McClure J, Jones G, et al. Predictors of outpatient medical appointment attendance among persons with HIV. AIDS Care. 1999;11:361–373.

23.Israelski D, Gore-Felton C, Power R, et al. Sociodemographic characteristics associated with medical appointment adherence among HIV-seropositive patients seeking treatment in a county outpatient facility. Prev Med. 2001;33:470–475.

24.McClure JB, Catz SL, Brantley PJ. Early appointment adherence among persons living with HIV. AIDS Behav. 1999;3:157–165.

25.Sherer R, Stieglitz K, Narra J, et al. HIV multidisciplinary teams work: support services improve access to and retention in HIV primary care. AIDS Care. 2002;14(suppl 1):S31–S44.

26.Ashman JJ, Conviser R, Pounds MB. Associations between HIV-positive individuals' receipt of ancillary services and medical care receipt and retention. AIDS Care. 2002;14(suppl 1):S109–S118.

27.Lo W, MacGovern T, Bradford J. Association of ancillary services with primary care utilization and retention for patients with HIV/AIDS. AIDS Care. 2002;14(suppl 1):S45–S57.

28.Freeman HP, Muth BJ, Kerner JF. Expanding access to cancer screening and clinical follow-up among the medically underserved. Cancer Pract. 1995;3:19–30.

29.Gary TL, Batts-Turner M, Bone LR, et al. A randomized controlled trial of the effects of nurse case manager and community health worker team interventions in urban African-Americans with type 2 diabetes. Control Clin Trials. 2004;25:53–66.

30.Kushel MB, Colfax G, Ragland K, et al. Case management is associated with improved antiretroviral adherence and CD4+ cell counts in homeless and marginally housed individuals with HIV infection. Clin Infect Dis. 2006;43:234–242.

31.Gardner LI, Metsch LR, Anderson-Mahoney P, et al. Efficacy of a brief case management intervention to link recently diagnosed HIV-infected persons to care. AIDS. 2005;19:423–431.

32.HIV/AIDS Bureau. Outreach: Engaging People in HIV Care. Rockville, MD: HRSA; 2006.

33.Bradford JB, Coleman S, Cunningham W. HIV System Navigation: an emerging model to improve HIV care access. AIDS Patient Care STDS. 2007;21(suppl 1):S49–S58.

34.Giordano TP, Gifford AL, White AC Jr., et al. Retention in care: a challenge to survival with HIV infection. Clin Infect Dis. 2007;44:1493–1499.

35.Das M, Chu PL, Santos GM, et al. Decreases in community viral load are accompanied by reductions in new HIV infections in San Francisco. 2010; PLoS One. 5:e11068.

36.DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed May 27, 2011.

37.Dieffenbach CW, Fauci AS. Universal voluntary testing and treatment for prevention of HIV transmission. JAMA. 2009;301:2380–2382.

38.Granich RM, Gilks CF, Dye C, et al. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. 2009;373:48–57.

39.Wagner BG, Kahn JS, Blower S. Should we try to eliminate HIV epidemics by using a "Test and Treat" strategy? AIDS. 2010;24:775–776.

40.Dodd PJ, Garnett GP, Hallett TB. Examining the promise of HIV elimination by "test and treat" in hyperendemic settings. AIDS. 2010;24:729–735.

41.Holtgrave DR. Potential and limitations of a "test and treat" strategy as HIV prevention in the United States. Int J Clin Pract. 2010;64:678–681.

42.Walensky RP, Paltiel AD, Losina E, et al. Test and treat DC: forecasting the impact of a comprehensive HIV strategy in Washington DC. Clin Infect Dis. 2010;51:392–400.

43.Charlebois ED, Das M, Porco TC, et al. The effect of expanded antiretroviral treatment strategies on the HIV epidemic among men who have sex with men in San Francisco. Clin Infect Dis. 2011;52:1046–1049.

44.Montaner JS, Lima VD, Barrios R, et al. Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study. Lancet. 2010;376:532–539.

45.Long EF, Brandeau ML, Owens DK. The cost-effectiveness and population outcomes of expanded HIV screening and antiretroviral treatment in the United States. Ann Intern Med. 2010;153:778–789.

46.Simoni JM, Amico KR, Pearson CR, et al. Strategies for promoting adherence to antiretroviral therapy: a review of the literature. Curr Infect Dis Rep. 2008;10:515–521.

47.Simoni JM, Pantalone DW, Plummer MD, et al. A randomized controlled trial of a peer support intervention targeting antiretroviral medication adherence and depressive symptomatology in HIV-positive men and women. Health Psychol. 2007;26:488–495.

48.Antoni MH, Carrico AW, Duran RE, et al. Randomized clinical trial of cognitive behavioral stress management on human immunodeficiency virus viral load in gay men treated with highly active antiretroviral therapy. Psychosom Med. 2006;68:143–151.

49.Sorensen JL, Haug NA, Delucchi KL, et al. Voucher reinforcement improves medication adherence in HIV-positive methadone patients: a randomized trial. Drug Alcohol Depend. 2007;88:54–63.

50.Remien RH, Stirratt MJ, Dolezal C, et al. Couple-focused support to improve HIV medication adherence: a randomized controlled trial. AIDS. 2005;19:807–814.

51.Bing EG, Burnam MA, Longshore D, et al. Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States. Arch Gen Psychiatry. 2001;58:721–728.

52.Ciesla JA, Roberts JE. Meta-analysis of the relationship between HIV infection and risk for depressive disorders. Am J Psychiatry. 2001;158:725–730.

53.Grimley DM, Bachmann LH, Jenckes MW, et al. Provider-delivered, theory-based, individualized prevention interventions for HIV positive adults receiving HIV comprehensive care. AIDS Behav. 2007;11(suppl):S39–S47.

54.Koester KA, Maiorana A, Vernon K, et al. Implementation of HIV prevention interventions with people living with HIV/AIDS in clinical settings: challenges and lessons learned. AIDS Behav. 2007;11(suppl):S17–S29.

55.Bachmann LH, Grimley DM, Chen H, et al. Risk behaviours in HIV-positive men who have sex with men participating in an intervention in a primary care setting. Int J STD AIDS. 2009;20:607–612.

56.Chen HT, Grimley DM, Waithaka Y, et al. A process evaluation of the implementation of a computer-based, health provider-delivered HIV-prevention intervention for HIV-positive men who have sex with men in the primary care setting. AIDS Care. 2008;20:51–60.

57.Marseille E, Shade SB, Myers J, et al. The cost-effectiveness of HIV prevention interventions for HIV-infected patients seen in clinical settings. J Acquir Immune Defic Syndr. 2011;56:87–94.

58.National Prevention Information Network. Enhanced Comprehensive HIV Prevention Planning and Implementation for Metropolitan Statistical Areas Most Affected by HIV/AIDS: Phase II. 2011. Available at: http://www.cdcnpin.org/scripts/Display/FundDisplay.asp?FundNbr=4308. Accessed May 27, 2011.

59.McKleroy VS, Galbraith JS, Cummings B, et al. Adapting evidence-based behavioral interventions for new settings and target populations. AIDS Educ Prev. 2006;18(suppl A):59–73.

60.Rotheram-Borus MJ, Klosinski LE, Etzel MA. Differences between proof-of-concept studies and effective implementation: routine, opt-out HIV testing in emergency departments. J Acquir Immune Defic Syndr. 2007;46:381–383.

61.Schackman BR. Implementation science for the prevention and treatment of HIV/AIDS. J Acquir Immune Defic Syndr. 2010;55(suppl 1):S27–S31.

62.Norton WE, Amico KR, Cornman DH, et al. An agenda for advancing the science of implementation of evidence-based HIV prevention interventions. AIDS Behav. 2009;13:424–429.

Source

High-Risk Groups Not Receiving Vaccinations Against Hep A, B

ISSUE: JUNE 2011 VOLUME: 62:06
by Christina Frangou

Chicago—Most adults who have chronic liver disease or type 2 diabetes do not receive the recommended vaccinations against hepatitis A and B viruses (HAV and HBV), even though these groups are considered at high risk for severe liver injury if they are acutely infected, said researchers at the 2011 Digestive Disease Week (DDW) meeting.

“Despite the fact that these people are at very high risk for severe liver injury, they are not vaccinated at the level you would expect,” said Zobair Younossi, MD, vice president of research for Inova Health System in Falls Church, Va., and executive director of the Center for Liver Diseases at Inova Fairfax Hospital. “We must consider other ways to distribute the vaccine, perhaps having it available in gastroenterology offices and primary care physicians’ offices,” he said.

Acute hepatitis A or B in patients with chronic hepatitis C can cause severe hepatic injury and a higher fatality rate than in patients without hepatitis C. Additionally, patients with type 2 diabetes—many of whom have undiagnosed nonalcoholic fatty liver disease (NAFLD)—also can have severe liver problems. HAV and HBV infections are vaccine-preventable diseases, and studies have confirmed the vaccines are safe and effective in patients with chronic liver disease or diabetes. As a result, several medical societies, including the American Association for the Study of Liver Diseases, the American College of Gastroenterology, the Infectious Diseases Society of America and the National Institutes of Health, recommend that all patients with chronic HCV who are not immune to HAV and HBV be vaccinated.

In the current study, investigators examined data from two cycles of the National Health and Nutrition Examination Survey (NHANES; 1999-2004 and 2005-2008), which included 22,466 adults. Of these, 3,239 individuals had chronic liver disease (hepatitis C, 12%; NAFLD, 68.7%; other liver diseases, 19.3%) and 2,480 individuals had type 2 diabetes. In the 2005-2008 period, 20% and 32% of patients with chronic liver disease reported receiving HAV and HBV vaccinations, respectively. For the same years, vaccination rates among diabetic persons were lower—15.6% for HAV and 21.8% for HBV.

Vaccination rates are rising. However, the high-risk groups are improving at the same pace as the general population. Overall, HAV vaccinations increased by approximately 6.9% from 1999-2004 to 2005-2008 in persons with chronic liver disease, and HBV vaccinations rose by 8.6%, both paralleling the increase in the control population. In individuals with diabetes, vaccination rates rose by 6.2% and 6.1% for HAV and HBV, respectively.

The low vaccination rates likely result from several factors. Health care providers may not appreciate the importance of HAV and HBV vaccinations in these high-risk patients. Additionally, there may be barriers to access; for instance, the vaccines are administered according to a fixed schedule over several months, and doctors’ offices may not be equipped to administer and store vaccines.

“This is an important public health issue, and public health policy makers need to develop strategies to make better vaccination mechanisms available to individuals with chronic liver disease,” Dr. Younossi remarked.

Health care providers should look at how drugstores, pharmacies, community health centers and other places could raise vaccination rates. Pharmacies could improve vaccination rates by providing the vaccine, Dr. Younossi suggested. “So a physician could write an order to have a vaccination done in a pharmacy, which could be easier to implement.”

On May 12, four days after Dr. Younossi presented his study, the U.S. Department of Health and Human Services released an action plan for prevention, care and treatment of patients with hepatitis. The plan calls for improvement in provider education, public awareness and access to health care services. Among the goals, “universal hepatitis A and hepatitis B vaccination for all vulnerable adults” is recommended.

By 2012, the department wants new strategies to expand access to the vaccines in the primary care setting. And by 2013, it wants to see expansion of vaccine delivery to pharmacies.

Source

Hepatitis C Treatment Changing Rapidly With Approvals of Two New Drugs

ISSUE: JUNE 2011 VOLUME: 62:06
by Rosemary Frei

On the heels of data presented at the 46th annual meeting of the European Association for the Study of the Liver (EASL) meeting and this year’s Digestive Disease Week meeting came the FDA approval of two new drugs designed to boost the effectiveness of peginterferon-ribavirin therapy for patients with chronic hepatitis C virus (HCV) genotype 1 infection. On May 13, the FDA approved boceprevir (Victrelis, Merck) followed days later by the approval of telaprevir (Incivek, Vertex/Tibotec), marking an eagerly anticipated revolution in the management of patients with HCV.

Cascade of Data

Data on the new drugs have not been in short supply. An article published last year in The New England Journal of Medicine on the use of telaprevir for previously treated patients with chronic HCV genotype 1 infection brought this new class of agents—inhibitors of HCV protease—into the spotlight (McHutchison JG et al. 2010;362:1292-1303). The results of the randomized, double-blind phase II study—known as PROVE3 (Protease Inhibition for Viral Evaluation 3)—indicated that the addition of telaprevir for as few as 12 weeks significantly increased sustained virologic response (SVR).

Two Phase III studies published in March indicated that boceprevir also boosted efficacy in as few as 24 weeks. Results of the RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2) trial indicated that the three-drug cocktail nearly tripled SVR rates in previously treated patients (Bacon BR et al. N Engl J Med 2011;364:1207-1217). Furthermore, data from the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial also showed that SVR rates in treatment-naïve patients are boosted significantly with the addition of boceprevir (Poordad F et al. N Engl J Med 2011;364:1195-1206).

Final results from the Phase III REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) trial also were presented at the EASL meeting. These data included all three major subgroups of patients who were not cured with a prior course of interferon-based therapy, including null responders.

All of the boceprevir studies were paid for by Merck, and the telaprevir studies were sponsored by Vertex and its collaborator, Tibotec.

Stephen H. Caldwell, MD, professor of medicine and director of hepatology, University of Virginia Health System, Charlottesville, pointed out that the emerging therapies for hepatitis C offer a significant increase in sustained viral eradication but also bring treatment complexity, side effects and expense.

“Emerging from the myriad of study names are new monitoring recommendations and prognostic indicators that will take time to really understand,” Dr. Caldwell said. “We should recall that the best-performed studies are closely monitored, often at a level unachievable in clinical practice. Clearly, the field has changed rapidly in a very short period of time. Careful assessment and thoughtful consideration will be key to optimizing success and minimizing failure,” he said.

Boceprevir Trials

In a poster presented at the EASL meeting, John M. Vierling, MD, and colleagues from Baylor College of Medicine in Houston analyzed the relationship between patients’ response during the lead-in period in the boceprevir trials and overall SVR rates. The investigators defined response during the lead-in period as at least a 1.0-log10 reduction in HCV RNA. Data from the SPRINT-2 and RESPOND-2 trials were combined for this study.

The researchers found a steady, stepwise increase in the percentage of patients achieving SVR after at least 24 weeks of triple-agent therapy based on the level of decrease in viral load after the four-week lead-in period with peginterferon-ribavirin alone. The pattern was particularly noticeable among non-black patients. Overall, the advantage of adding boceprevir was greatest for patients with less responsiveness to interferon.

“Patients in the boceprevir arms with a poor response to interferon had sufficiently high rates of SVR as compared with the control group. … [This] dispels concern that the addition of boceprevir to the treatment regimen would be the equivalent of functional monotherapy,” the investigators noted. “However, patients who have a poor response to the interferon may need to be monitored closely to determine who may benefit from better therapies, once they are available.”

They add that conversely, addition of boceprevir may not boost SVR rates among patients with undetectable HCV RNA levels after the lead-in period, but that “in the majority of these patients, total treatment duration is shortened to 28 weeks.”

The four most common treatment-related adverse events (AEs) in the RESPOND-2 and SPRINT-2 studies were fatigue, headache, nausea and anemia. In RESPOND-2, treatment discontinuation due to anemia occurred in 3% of boceprevir patients in 48-week treatment only. None of the controls discontinued due to anemia. The respective numbers for SPRINT-2 were 2%, 2% and 1%. Erythropoietin was allowed for the treatment of anemia at the discretion of the investigators, and in RESPOND-2 was used by 41% and 46% of boceprevir patients in the response-guided and 48-week treatment arms, respectively, compared with 21% of patients in the control arm. In SPRINT-2, the respective numbers were 43%, 43% and 24%. (P values were not supplied.)

Fred Poordad, MD, chief of hepatology and liver transplantation at the Comprehensive Transplant Center at Cedars-Sinai Medical Center in Los Angeles, and lead investigator of the SPRINT-2 trial, gave a talk at the EASL meeting outlining the utility of using an interleukin (IL)-28B polymorphism as a baseline predictor of four- and eight-week response to triple-agent therapy. Dr. Poordad and colleagues from the SPRINT-2 and RESPOND-2 trials examined on SVR rates in patients with three different IL-28B polymorphisms: cysteine–cysteine, thymine–thymine and cysteine–thymine. They determined that the cysteine–cysteine polymorphism is associated most strongly with SVR response; patients with this polymorphism may be eligible for short-duration therapy.

Dr. Poordad’s team also found that lead-in response is a stronger predictor of SVR than any other single baseline characteristic, including IL-28B polymorphism. They concluded that because IL-28B polymorphism status and lead-in response “are powerful predictors of SVR,” the optimal approach may be to use both.

“Taken together, these data showed that the addition of boceprevir to peginterferon and ribavirin achieved significantly higher SVR rates in patients with chronic HCV genotype 1 compared with peginterferon and ribavirin alone, and that nearly half of all patients were eligible to receive a shorter duration of therapy,” Dr. Poordad said.

Telaprevir Trials

The REALIZE trial was a randomized, double-blind, placebo-controlled study of people who were previously treated unsuccessfully for HCV infection.

Subjects were randomized 2:2:1 into two telaprevir-based treatment arms—a “lead-in” arm and a “simultaneous-start” arm—and a control arm, which comprised 48 weeks of treatment with peginterferon-ribavirin alone. The lead-in arm included a four-week lead-in period of treatment with peginterferon-ribavirin followed by the addition of telaprevir for 12 weeks, then followed by 32 weeks of treatment with peginterferon-ribavirin alone. The simultaneous-start arm involved 12 weeks of triple-combination therapy, followed by 36 weeks of peginterferon-ribavirin alone.

Forty-eight percent (316 of 662) of the patients had advanced liver fibrosis or cirrhosis, and 89% (586 of 662) had a high HCV RNA load (≥800,000 IU/mL) at study entry.

The primary end point in all three groups was SVR. The results were analyzed based on three subgroups of patients: patients with undetectable levels of HCV RNA during at least 42 weeks of prior treatment that later became detectable (prior relapsers); patients who achieved at least a 2-log10 decrease in HCV RNA by week 12 of treatment but who did not achieve undetectable levels by week 24 (prior partial responders); and, those who did not achieve a 2-log10 decrease in HCV RNA by week 12 of treatment (prior null responders).

SVR rates for all patients in the telaprevir treatment arms were significantly greater compared with patients in the control group (Table; P<0.001). This held true for patients in the two telaprevir-containing arms combined, among which 86% (245 of 286) of the prior relapsers achieved SVR, 57% (55 of 97) of prior partial responders had an SVR and 31% (46 of 147) of the prior null responders had an SVR.

“We believe the data showed that an immediate start of a 12-week telaprevir-based regimen substantially improved viral cure rates in all three major subgroups of people who were not cured with currently available medicines,” said Robert Kauffman, MD, PhD, senior vice president and chief medical officer, Vertex Pharmaceuticals.

The most common AEs in the telaprevir studies were fatigue, pruritus, nausea, headache, rash and anemia. Anemia occurred in 36% of patients in the treatment lead-in arm, 30% of subjects in the simultaneous-start arm and 15% in the control arm; erythropoietin treatment was not allowed in the study. Rash was present in 36% of patients in the lead-in arm, 37% in the simultaneous-start arm and 19% of the control arm. Three percent of patients in the telaprevir-treatment arms discontinued all treatment because of anemia and 3% did so because of rash. (No P values were provided.)

Retrospective analyses of IL-28B polymorphisms in patients treated with telaprevir also were presented at the EASL meeting. Data from the ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir) trial, a Phase III study of treatment-naïve patients with HCV, indicated that the cysteine–cysteine variation of the IL-28B polymorphism is associated with the highest SVR rates, at 90% compared with 73% among patients with the thymine–thymine polymorphism and 71% among individuals with the cysteine–thymine polymorphism.

Retrospective analysis of data from REALIZE indicated that the cysteine–cysteine variant also is associated with the highest SVR rates, at 79% compared with 61% for the thymine–thymine polymorphism and 60% for the cysteine–thymine polymorphism.

Additionally, interim results from a Phase II study of treatment-naïve HCV patients with the combination of telaprevir, peginterferon-ribavirin and the polymerase inhibitor VX-222 (Vertex) also were presented at the meeting. Of patients who received a combination of the four agents, 90% had undetectable HCV RNA after 12 weeks. In another group of patients who received a combination of the four agents with a lower dose of VX-222, 83% showed undetectable levels of HCV RNA.

“Boceprevir and telaprevir will greatly improve our ability to eradicate hepatitis C from both treatment-naïve as well as treatment-experienced patients,” commented Donald M. Jensen, MD, professor of medicine and director of the Center for Liver Disease, University of Chicago Medical Center, who wrote an editorial accompanying the published results of RESPOND-2 and SPRINT-2 (N Engl J Med;2011;364:1272-1274). “However, this success will come at a cost—an increase in side effects and some increase in treatment complexity.”

Series Editor
 
Tarun Mullick, MD
Clinical Faculty
Rush-Copley Medical Center
Aurora, Illinois
Clinical Staff
Delnor Hospital
Geneva, Illinois
Provena Mercy Medical Center
Aurora, Illinois

Commentary by Dr. Mullick

For the past decade, treatment with pegylated interferon and ribavirin for hepatitis C virus (HCV) genotypes 2 and 3 was able to provide a sustained virologic response (SVR) of approximately 80% after 24 weeks of treatment. However, the more difficult to treat HCV genotype 1 not only requires 48 weeks of treatment with pegylated interferon and ribavirin, but also is associated with an SVR ranging from 40% to 50%.

The problem with pegylated interferon and ribavirin and prior therapies was that they do not target the virus directly in a way that effectively puts the virus in a dormant state. Until now, therapies for patients with HCV genotype 1 infection were limited in their efficacy.

With the arrival of two new HCV protease inhibitors, telaprevir and boceprevir, we now have drugs available that target the virus in a more direct and effective manner. In combination with pegylated interferon and ribavirin, the new protease inhibitors cut the duration of treatment to 24 weeks and achieve an SVR approaching 80%!

The potential for side effects exists for each of the new drugs, with rash and bone marrow–related issues among them. Overall, however, this is the largest breakthrough in hepatitis C treatment in a decade.

By the time other future therapies become available, these medications will likely have treated 80% of patients with HCV infection. These drugs have the potential to dramatically reduce the number of HCV patients who develop cirrhosis, liver cancer and who require liver transplant for this disease.

Fantastic!

Source