June 30, 2011

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.

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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

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!

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Fewer Complications With NAFLD Than Hepatitis C Virus

Last Updated: June 30, 2011

THURSDAY, June 30 (HealthDay News) -- Patients with nonalcoholic fatty liver disease (NAFLD) with advanced fibrosis or cirrhosis may have fewer liver-related complications and less hepatocellular cancer than patients with hepatitis C virus (HCV) infection, but may have similar overall mortality, according to a study published online June 17 in Hepatology.

Neeraj Bhala, M.B.Ch.B., M.R.C.P., from the University of Oxford in the United Kingdom, and colleagues examined the long-term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis. A cohort of 247 patients with NAFLD, followed up for an average of 85.6 months, and a second cohort of 264 patients with HCV infection, who were either naive or non-responders to treatment, and who were followed up for 74.9 months, were included in the study. Both cohorts were Child-Pugh class A, with liver biopsy-confirmed advanced fibrosis or cirrhosis.

The investigators found that there were 19.4 percent liver-related complications and 13.4 percent deaths or liver transplants in the NAFLD cohort. There were 16.7 percent liver-related complications and 9.4 percent deaths or liver transplants in the HCV cohort. The NAFLD cohort had significantly lower incidence of liver-related complications, including incident hepatocellular cancer, than the HCV cohort, after adjusting for age and gender. Both cohorts had similar incidence rates of cardiovascular events and overall mortality.

"Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver-related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality," the authors write.

Abstract
Full Text (subscription or payment may be required)

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June 30, 2011 09:00 AM Eastern Daylight Time

However, Less Than Half of Surveyed Managed Care Organizations Plan To Provide Reimbursement for Either Agent for Use in Treatment Naive HCV1 Patients, According to a New Report from Decision Resources

BURLINGTON, Mass.--(BUSINESS WIRE)--Decision Resources, one of the world’s leading research and advisory firms for pharmaceutical and healthcare issues, finds that more than two-thirds of surveyed U.S. clinicians plan to prescribe Vertex/Johnson & Johnson/Mitsubishi Tanabe’s Incivek and Merck/Roche’s Victrelis to patients with treatment-naive hepatitis C virus genotype 1 (HCV1), and half of surveyed physicians indicate they will add Incivek or Victrelis to an HCV1 patient’s existing pegylated-interferon(peg-IFN)/ribavirin regimen. In May 2011, Incivek and Victrelis were approved as treatments for hepatitis C virus by the U.S. Food and Drug Administration.

The new U.S. Physician & Payer Forum report entitled Hepatitis C Virus: How Will The Launch of Novel Antivirals Influence U.S. Physician and Payer Attitudes Towards Treatment and Reimbursement? also finds that, among the surveyed clinicians who expect to prescribe Incivek to more HCV1 treatment-naive patients than Victrelis, 64 percent cite the high sustained virologic response (SVR) rate of Incivek-based regimens as the most important factor in their prescribing decisions. Similarly, the largest proportions of managed care organizations’ (MCO) pharmacy directors who expect to add Incivek to their formularies rank SVR in nonresponders and in treatment-naive patients as the most important factors driving the inclusion of Incivek in their formularies.

“Surveyed physicians estimate that an Incivek-based regimen will be used to treat more than half of all HCV1 patients and will be used in 44 percent of HCV2/3 nonresponders,” said Decision Resources Analyst LaTese Briggs, Ph.D. “Additionally, only 11 percent of surveyed clinicians expect to prescribe Victrelis over Incivek—of this small minority, 45 percent cite the possibility of a shorter treatment duration in HCV1 nonresponders along with acceptable SVR rates as the most influential factors in their decision to prescribe Victrelis over Incivek.”

The report also finds that while clinicians plan to use Incivek in more than half of HCV1 treatment-naive patients, less than half of surveyed MCOs plan to reimburse Incivek-based therapy in this subpopulation. Among surveyed pharmacy directors who expect to cover Incivek, only 47 percent plan to reimburse this agent for HCV1 treatment-naive patients. According to 68 percent of surveyed MCOs, Incivek will more likely be reimbursed for treatment of HCV1 nonresponders. Similar to Incivek, more than three-quarters of surveyed MCOs who expect to cover Victrelis, plan to reimburse it for HCV1 nonresponders, but only 39 percent expect to provide reimbursement for Victrelis in HCV1 treatment-naive patients.

About Decision Resources

Decision Resources (http://www.decisionresources.com/) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources, Inc. company.

About Decision Resources, Inc.
Decision Resources, Inc. is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources, Inc. at http://www.decisionresourcesinc.com/.

All company, brand, or product names contained in this document may be trademarks or registered trademarks of their respective holders.

Contacts
Decision Resources, Inc.
Christopher Comfort, 781-993-2597
ccomfort@dresources.com

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June 29, 2011

Articles in Press

F. Violia, S. Basilia, V. Raparellia, P. Chowdaryb, A. Gattb, A.K. Burroughsc

Received 28 February 2011; received in revised form 20 June 2011; accepted 21 June 2011. published online 29 June 2011.
Accepted Manuscript

Abstract

Patients with cirrhosis can have abnormalities in laboratory tests reflecting changes in primary haemostasis, including bleeding time, platelet function tests, markers of platelet activation and platelet count. Such changes have been considered particularly relevant in the bleeding complications that occur in cirrhosis.

However, several studies have shown that routine diagnostic tests, such as platelet count, bleeding time, PFA-100, thrombelastography are not clinically useful to stratify bleeding risk in patients with cirrhosis. Moreover, treatments used to increase platelet count or to modulate platelet function could potentially do harm. Consequently the optimal management of bleeding complications is still a matter of discussion.

Moreover, in the last two decades there has been an increased recognition that not only bleeding but also thrombosis complicates the clinical course of cirrhosis. Thus, we performed a literature search looking at publications studying both qualitative and quantitative aspects of platelet function to verify which primary haemostasis defects occur in cirrhosis. In addition, we evaluated the contribution of qualitative and quantitative aspects of platelet function to the clinical outcome in cirrhosis and their therapeutic management according to the data available in the literature.

From the detailed analysis of the literature it appears clear that primary haemostasis may not be defective in cirrhosis, and a low platelet count should not necessarily be considered as an automatic index of an increased risk of bleeding. Conversely, caution should be observed in patients with severe thrombocytopenia where its correction is advised if bleeding occurs and before invasive diagnostic and therapeutic procedures.

Keywords: Liver Disease, Thrombocytopenia, Thrombocytopathy, Bleeding, Platelets

No full text is available. To read the body of this article, please view the PDF online.

a Divisione di I Clinica Medica, Sapienza- University of Rome, Rome, Italy
b Haemophilia Centre & Thrombosis Unit, Royal Free Hospital Hampstead NHS Trust, London, UK
c The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery UCL London, UK

PII: S0168-8278(11)00499-5
doi:10.1016/j.jhep.2011.06.008
© 2011 Published by Elsevier Inc.

Source
Articles in Press

Mauricio F. Silvaa, Morris Shermanb

Received 11 April 2011; received in revised form 17 May 2011; accepted 18 May 2011. published online 28 June 2011.
Accepted Manuscript

Abstract

Liver transplantation is a well-established treatment in a subset of patients with cirrhosis and hepatocellular carcinoma. The Milan criteria (single nodule up to 5cm, up to 3 nodules none larger than 3cm, with no evidence of extrahepatic spread or macrovascular invasion) have been traditionally accepted as standard of care. However, some groups have proposed that these criteria are too restrictive, and exclude some patients from transplantation who might benefit from this procedure. Transplanting patients with tumors beyond the established criteria falls into two categories, those whose tumors are beyond the Milan criteria at presentation without the use of treatment prior to transplantation (expanded criteria), and those in whom treatment allows the MC to be fulfilled (down-staging). Currently, however, there is no international consensus regarding these approaches in clinical practice. The purpose of this systematic review is to clarify this debate through a critical analysis of available data. Finally, some comments on predictive factors apart from morphological characteristics are also addressed.

Keywords: Hepatocellular carcinoma, Liver transplantation, Expanded criteria, Down-staging, Milan criteria, Systematic review, Evidence based medicine

No full text is available. To read the body of this article, please view the PDF online.

a Department of HBP Surgery and Transplantation, Santa Casa General Hospital, Porto Alegre, Brazil
b University of Toronto, University Health Network Toronto, ON, Canada

PII: S0168-8278(11)00495-8
doi:10.1016/j.jhep.2011.05.012
© 2011 Published by Elsevier Inc.

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Viral Load Tied to Vertical Transmission of Hepatitis C

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Genetic variation in IL28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV infected children

"In view of the data presented, we believe it is necessary to make a clear distinction between the risk factors of HCV-VT and of chronic infection. We confirm that viral load and HIV co-infection are the only risk factors involved in HCV-VT. On the other hand, the viral genotype non-1 and the infant's IL28B CC Rs12979860 polymorphism are associated with HCV spontaneous clearance. Our data are the first to account for HCV virus clearance and may provide important information about protective immunity to HCV."

Last Updated: May 23, 2011.

Hepatology

Accepted Article (Accepted, unedited articles published online for future issues)

High maternal viral load is associated with vertical transmission of hepatitis C virus, but polymorphisms in interleukin 28B are not, according to a study published online March 16 in Hepatology.

MONDAY, May 23 (HealthDay News) -- High maternal viral load is associated with vertical transmission of hepatitis C virus (HCV-VT), but polymorphisms in interleukin 28B (IL28B) are not, according to a study published online March 16 in Hepatology.

Angeles Ruiz-Extremera, M.D., from San Cecilio University Hospital in Granada, Spain, and colleagues assessed the role of a single nucleotide polymorphism on IL28B in HCV-VT and the spontaneous clearance of HCV among infected infants. Mothers recruited for the study included 112 who were HCV-RNA positive/HIV negative and 33 HCV-RNA negative/HCV-antibody positive with 142 and 43 children, respectively. Children underwent testing for HCV-RNA at birth and regularly until the age of 6 years. Single nucleotide polymorphism at IL28B was determined in mothers and children. The occurrence of HCV-VT was assumed when children presented HCV-RNA positive in two subsequent blood samples.

The investigators found that 61 percent of the 31 mothers with the CC polymorphism and 82 percent of the 68 mothers with non-CC polymorphism were HCV-RNA positive. Among infants born to HCV-RNA positive mothers, 20 percent acquired HCV infection, but only 9 percent were chronically infected. No HCV-VT was seen in HCV-RNA negative women, and the rate was increased in mothers with higher HCV viremia. Neither maternal nor child IL28B status was correlated with increased risk of HCV-VT. Genotype non-1 and genotype CC of the IL28B were the factors influencing viral clearance among the infected children. Child CC polymorphism was the sole predictor of HCV clearance in HCV genotype-1.

"High maternal viral load is the only predictive factor of HCV-VT. IL28B plays no role in HCV-VT," the authors write.

Abstract

The vertical transmission of Hepatitis C Virus (HCV-VT) is a major route of HCV infection in children, but the risk factors remain incompletely understood. This study analyses the role of IL28B in HCV-VT and in the spontaneous clearance of HCV among infected infants. Between 1991 and 2009, 145 mothers were recruited to this study: 100 were HCV-RNA+ve/HIV-ve, with 128 children, and 33 were HCV-RNA-ve/HCV antibody+ve, with 43 children. The infants were tested for HCV-RNA at birth and at regular intervals until the age of 6 years. IL28B (single nucleotide polymorphism rs12979860) was determined in the mothers and children. HCV-VT was assumed when children presented HCV-RNA+ve in two subsequent blood samples. HCV-VT infected infants were categorized as: (A) transient viremia with posterior HCV-RNA-ve and without serum-conversion; (B) persistent infection with serum-conversion. Of the 31 mothers with CC polymorphism, 19(61%) were HCV-RNA+ve whereas among the 68 mothers with non-CC polymorphism, 56(82%) were HCV-RNA+ve. 26 of 128(20%) infants born to the HCV-RNA+ve mothers acquired HCV infection, but only 9(7%) were chronically infected. The rate of HCV-VT was higher among the mothers with higher HCV viremia. No HCV-VT was detected in the HCV-RNA-ve women. Neither the mothers' nor the children's IL-28 status was associated with an increased risk of HCV-VT. The factors influencing viral clearance among the infected children were genotype non-1 and genotype CC of the IL28B. In logistic regression, child CC polymorphism was the only predictor of HCV-clearance in HCV genotype-1.

CONCLUSIONS:

High maternal viral load is the only predictive factor of HCV-VT. IL28B plays no role in HCV-VT, but IL28B CC child polymorphism is associated independently with the spontaneous clearance of HCV genotype-1 among infected children. (HEPATOLOGY 2011.)

Discussion

Vertical transmission of Hepatitis C Virus represents the mayor cause of paediatric HCV infection today, and in industrialized countries it is the most common cause of chronic liver disease in children. About 10-15% of those who are chronically infected might develop cirrhosis and eventually hepatocellular carcinoma (16, 17). HCV prevalence in pregnant women is similar to that of the general population and in general, most HCV-infected pregnant women do not have obstetric complications. At present, there are no antiviral treatment recommendations for HCV-infected women during pregnancy, or guidelines for the prevention of vertical transmission (18). Although persistent transmission of HCV from infected mothers to their infants is reported in 4-8% of cases (chronic HCV children), transient HCV perinatal infection also occurs, with a prevalence of about 14-17% (19, 20). Moreover, the maternal-infant transmission of HCV is more frequent than is generally reported, taking into account that spontaneous HCV-RNA clearance among children is more common than among adults and that in many studies the follow up of infants is incomplete; moreover, in many cases only limited data, corresponding to the first years of life, are presented (21). IFNα is currently the approved drug for hepatitis C treatment for the paediatric population. Combination therapy with IFNα or pegylated IFNα plus ribavirin has recently been approved by the US FDA-EMEA for children older than 3 years with chronic HCV infection, and clinical trials are in progress (3, 22). Although most children are asymptomatic and the associated liver damage appears to be less severe in children than in adults, they have a significantly poorer health status than community controls (23), which suggests there is a need for the services currently available for adult HCV patients to be extended to support the families of children with HCV.

Conflicting data have been reported regarding the possible role of the level of maternal HCV viremia. Some studies have shown that a high concentration of serum HCV-RNA is associated with a higher risk of transmission, although no specific cut-off value predicting or excluding transmission has been defined (11). However, other studies have found no such association, with a considerable overlap in concentrations of HCV-RNA between transmitting and non-transmitting mothers (1, 24). Moreover, maternal co-infection with HCV and human immunodeficiency virus (HIV) is associated with high maternal HCV-RNA and with a higher risk of transmission (18, 25). In the present study, we found that both the HCV-RNA concentration (over 600,000 UI/mL) and maternal co-infection with HIV were associated with a higher risk of HCV-VT. The infected infants were not HCV-RNA positive at birth but all became so within 2-4 months. These data indicate that HCV maternal-foetal transmission did not occur during gestation and, therefore, that the infants were infected during the birth. Most of the infected children were asymptomatic despite high levels of alanine transaminase, compatible with acute hepatitis. The infants that cleared the HCV virus recovered normal alanine aminotransferase levels. With respect to the type of birth, there was no significant decrease in HCV-VT among the mothers who gave birth by caesarean section versus those who did not. The data on the effect of caesarean section on the risk of HCV perinatal transmission are heterogeneous and high-quality studies of this question have not been reported. A recent meta-analysis including 8 studies and 641 mother-infant pairs suggests that caesarean section does not decrease perinatal HCV transmission from HCV-RNA+ve/HIV-ve mothers to infants (8). No relationship between HCV-VT and the maternal HCV genotype has been found. On the other hand, when we studied spontaneous clearance (children with transient viremia) vs chronic infection in infected infants, the HCV viral genotype was associated with a higher risk of chronic infection. Thus, the rate of HCV chronicity was higher for infants with viral genotype 1 than for those with genotype non-1, a finding that is in accordance with the results of Bortolotti et al. (6). The role of viral genotype and its association with HCV spontaneous clearance and chronic infection should be explored further.

The HCV-VT risk factors that have been most intensively studied, to date, are viral factors, maternal characteristics and birth mode. However, immunogenetic influence has been poorly investigated and mainly confined to HLA-class II serological polymorphisms, because of their central role in the adaptive response. Nevertheless, it has been suggested that the role of the immune defence system, as well as the relevance of the genetic background, could better explain the pathogenesis of HCV infection, and these factors have been examined (10, 11). In adult patients, genetic variations in the interleukin 28B (IL28B) gene, an innate cytokine, have been associated with the response to interferon-alpha/ribavirin therapy and spontaneous clearance in HCV genotype 1 (26-28). For this reason, we evaluated the role of IL28B polymorphism in HCV genotype 1 vertical transmission, transient viremia and chronic infection in infants. This is the first study that attempts to describe both HCV-VT and the spontaneous clearance of HCV, taking into account the influence of IL28B polymorphism in mothers and children. The data obtained indicate that the IL28B genotype of mothers and children does not influence HCV-VT. Nevertheless, in the chronic infection study, 83% of the infants with the CC genotype exhibited spontaneous clearance (transient viremia) versus only 22% of the children with a non- CC genotype. On the other hand, the maternal IL28B genotype did not influence HCV chronic infection. Multivariate analysis identified the infant's Rs12979860 CC IL28B genotype as the only factor independently associated with the spontaneous clearance of HCV. To the best of our knowledge, the present study is the first one to identify IL28B Rs12979860 polymorphism as a predictor of HCV spontaneous clearance in infants infected with HCV genotype 1 by vertical transmission. More information is now needed to understand the mechanisms that underlie this association, as well as the clinical impact of IL28B polymorphisms on HCV infection.

The multivariate analysis performed clearly shows the distinction between the risk factors in HCV-VT and in chronic infection. In HCV-VT, a high HCV viral load was independently associated with HCV-VT, thus confirming the bivariate analysis and the data previously published, by ourselves and by others. These data suggest that the maternal characteristics are more important in HCV-VT than are those of the infants. However, in the chronic HCV infection study, the multivariate analysis showed that the only factor independently associated with HCV clearance was the infants' IL28B genotype, which confirmed our hypothesis that in infected infants, the host's immunogenic influence is crucial to the HCV viral response.

Finally, all retrospective analyses have inherent limitations, but we have tried to minimize their effects. The standard method of HCV determination changed during the patient inclusion period but this factor was controlled by using the same PCR technique on all the patients studied, using a stored blood sample. Furthermore, the standard care of HIV and HCV patients also changed during the patient inclusion period; however, in this study the risk factors among the HIV negative mothers (Study Cohort) were identified. According to standard protocols for VHC pregnant women, no VHC treatment should be applied during the pregnancy, and thus the changes in standard care for HCV patients do not affect our study. In view of the data presented, we believe it is necessary to make a clear distinction between the risk factors of HCV-VT and of chronic infection. We confirm that viral load and HIV co-infection are the only risk factors involved in HCV-VT. On the other hand, the viral genotype non-1 and the infant's IL28B CC Rs12979860 polymorphism are associated with HCV spontaneous clearance. Our data are the first to account for HCV virus clearance and may provide important information about protective immunity to HCV.

Source
K. Ellingson; D. Seem; M. Nowicki; D. M. Strong; M. J. Kuehnert

Posted: 06/27/2011; American Journal of Transplantation. 2011;11(6):1201-1208. © 2011 Blackwell Publishing

Abstract and Introduction

Abstract

To prevent unintentional transmission of bloodborne pathogens through organ transplantation, organ procurement organizations (OPOs) screen potential donors by serologic testing to identify human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. Newly acquired infection, however, may be undetectable by serologic testing. Our objective was to estimate the incidence of undetected infection among potential organ donors and to assess the significance of risk reductions conferred by nucleic acid testing (NAT) versus serology alone. We calculated prevalence of HIV and HCV—stratified by OPO risk designation—in 13 667 potential organ donors managed by 17 OPOs from 1/1/2004 to 7/1/2008. We calculated incidence of undetected infection using the incidence-window period approach. The prevalence of HIV was 0.10% for normal risk potential donors and 0.50% for high risk potential donors; HCV prevalence was 3.45% and 18.20%, respectively. For HIV, the estimated incidence of undetected infection by serologic screening was 1 in 50 000 for normal risk potential donors and 1 in 11 000 for high risk potential donors; for HCV, undetected incidence by serologic screening was 1 in 5000 and 1 in 1000, respectively. Projected estimates of undetected infection with NAT screening versus serology alone suggest that NAT screening could significantly reduce the rate of undetected HCV for all donor risk strata.

Background

Transmission of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) can occur through solid organ transplantation.[1–4] Strategies to reduce transmission of these bloodborne pathogens from donor to recipient include assessing donor medical and behavioral risk, and laboratory testing for anti-HIV and anti-HCV seroreactivity in all potential organ donors. For most laboratory tests, there are window periods during which infection cannot be detected in donors with newly acquired infection. Compared with serologic testing, nucleic acid-amplification tests (NAT) shorten the window period through detection of the virus in plasma. In 2007 a donor, who was found to be nonreactive for HIV and HCV by routine serologic screening, was later found to be NAT-positive after four organ recipients were infected with HIV and HCV.[5] This incident underscored the need for a better understanding of the prevalence of HIV and HCV among potential organ donors and for evaluation of more sensitive screening tests to reduce the risk of undetected infection.

Estimates of HIV and HCV infection rates during the window period for serologic testing (i.e. undetected infection) were recently reported in US blood and tissue donors but have not been estimated for organ donors. For first-time blood donors, 1 in 3.1 million donations for HIV and 1 in 270 000 for HCV were nonreactive by serology assays, but positive by NAT.[6] The estimated risk of undetected infection among tissue donors for serologic testing is much higher: 1 in 55 000 for HIV and 1 in 42 000 for HCV.[7] The US Food and Drug Administration (FDA) currently mandates NAT screening for all blood and tissue donors for HIV and HCV, but no government agency mandates NAT screening for organ donors.[8] As of 2008, approximately one-half of the 58 US organ procurement organizations (OPOs) voluntarily performed HIV and HCV NAT on all or at least some subset of their potential donors.[9]

When transplant centers decide whether to accept an organ for transplantation, they rely on serologic test results as well as the 'high risk' designation assigned by OPOs during donor evaluations. OPOs are required to document the potential donor's infectious risk status utilizing risk criteria for HIV transmission outlined in the PHS 1994 guidelines.[10] Many OPOs have also used these criteria to evaluate risk for hepatitis virus transmission, as indicated by donor medical-behavioral history questionnaires (Appendix 1). A 2008 survey of US OPOs reported that, on average, 7.7% of an OPO's donors with organs recovered for transplantation, were designated as high risk, ranging from 2.3 to 26.1%.[11] Because transplants can be life saving, recipients and transplant surgeons may accept organs from high risk donors due to the shortage of available organs for transplantation; in 2008, 9465 candidates died or became too ill to benefit from transplantation while waiting for an available organ.[12] Organ acceptance may be influenced by type of organ needed, type of risk factor identified, medical health status of the candidate and laboratory testing results.

To appropriately weigh the risk of unintentional infection with HIV or HCV against the risk of delayed transplant, providers and patients must be able to reasonably assess risk. Currently there are no published studies that estimate the risk of undetected infection among potential organ donors by serologic testing in the United States. The objectives of this study were to (1) calculate the prevalence of HIV and HCV among a large subset of potential organ donors in the United States; (2) estimate the incidence of HIV and HCV among potential organ donors during the window periods for serologic and NAT screening.

Materials and Methods

Study Population

A sample of 17 of the 58 OPOs in the United States participated voluntarily in this study; these 17 OPOs manage over half of US organ donors.[12] Participating OPOs constituted a convenience sample of OPOs that submitted serologic screening results through three large reference laboratories to the CDC for the designated study period. Serologic tests were performed at local OPO, hospital or reference laboratories. The geographic distribution of participating OPOs was concentrated in the northeast, mid-Atlantic and western states, including Alaska (Figure 1). Nucleic acid testing results were not available for the majority of participating OPOs and were available for only a fraction of donors within OPOs performing NAT; thus NAT results were not considered for analysis in this study.


Figure 1.
Geographic distribution of the 17 organ procurement organizations (OPOs) participating in the study; participating OPOs fully covered states shaded dark gray and partially covered states shaded light gray, representing over 50% of all US organ donors.

Demographic and serologic data from January 2004 to July 2008 were requested from participating OPOs for all potential organ donors, including those who were consented but subsequently had no organs recovered. Serologic data collected from participating OPOs included anti-HIV and anti-HCV test results. Western blot (WB) confirmatory testing results for anti-HIV and recombinant immunoblot assay (RIBA) confirmatory tests for anti-HCV were also collected when available. Data on high risk designation, as determined by the OPO based on criteria presented in Appendix I, were collected. Participating OPOs also submitted information on the assay and generation of the specific tests used over the study period. All potential donors for whom data were requested had legal consent for organ donation and serologic test results. This study was determined to be exempt from human subjects review by the institutional review board at the Centers for Disease Control and Prevention in August, 2008.

Prevalence of Bloodborne Pathogens Among Potential Organ Donors

To calculate crude prevalence for HIV and HCV among potential donors, the number of positive results for a given serologic test was divided by the total number of potential donors tested. To account for false positive serologic results, adjustment factors were created directly from data submitted by OPOs from subsets of donors with WB or RIBA confirmatory tests available. For example, within the subset of HIV-positive serologic tests with WB availability, the number of positive anti-HIV serologies with positive WB results was divided by the number of all HIV-positive serologies with WB positive, negative or indeterminate results to calculate a conservative adjustment factor; a more liberal adjustment factor using both positive and indeterminate WB results as the numerator was calculated. The same process was followed for HCV, using available RIBA testing to create conservative and liberal adjustment factors. For HIV, there were 11 antibody-reactive cases for which confirmatory WB tests were available; 4 (0.36) had positive WB results, and 2 (0.18) had indeterminate results. For HCV, there were 183 antibody-reactive cases with RIBA confirmatory tests available; 142 (0.78) were RIBA positive, and 11 (0.06) were RIBA indeterminate. The adjustment factors were determined to be the midpoint of the conservative and liberal estimates: 0.45 for HIV and 0.81 for HCV.

The prevalence of HIV and HCV among potential organ donors was calculated for all potential donors and for donors stratified by OPO risk designation. Designations included 'normal risk' (i.e. actively designated as not 'high risk'), 'high risk' and 'missing risk' (i.e. risk status was either not recorded or not available for this study). The raw prevalence was multiplied by an adjustment factor (described above) to reflect prevalence adjusted for false positive serologic tests. Credible intervals surrounding the prevalence estimates were generated using Monte Carlo simulations for each pathogen and risk category. For the simulations, the number of tests reactive by serology was assigned a Poisson distribution. The adjustment factors were assigned triangular distributions with minimum and maximum values reflecting the conservative and liberal adjustment factor calculations: (0.36–0.55) for HIV and (0.78–0.84) for HCV. Values were drawn from these probability distributions for 10 000 repetitions, resulting in 95% credible intervals.

Estimating Incidence of Undetected Infection Among Potential Organ Donors

Incidence of undetected HIV and HCV infection in potential organ donors was calculated using the incidence-window period model originally developed for blood donors, which involves multiplying the incidence of infection (i.e. the yearly rate of newly acquired infection) in the donor population by the length of the window period.[13–16] The infectious window period is defined as the time after infectivity when the virus reaches a sufficient level in plasma to be transmissible up to the time of detection by NAT or serologic screening methods.[14,16,17] The incidence-window period model was recently modified for estimation of undetected infection in the tissue donor population in the United States and to organ and tissue donor populations in Canada.[7,16] Incidence in the blood donor population can be determined by examining seroconversion in repeat blood donors.[4] Since there are no repeat donations in the deceased potential organ donor population, incidence must be estimated by extrapolating from blood donor data.

Estimating the yearly incidence of HIV and HCV among potential organ donors required making projections from incidence estimates in blood donors during the same time period. It was assumed that prevalence differences between the organ donors in this study and blood donors in published literature would reflect differences in incidence. Thus, the ratio of organ donor prevalence to published blood donor prevalence was multiplied by the published incidence in blood donor population to attain the incidence in the study population of organ donors. Published incidence and prevalence rates from a population of blood donors who had donated to Red Cross Blood Services from 2007 and 2008 were used to make this calculation.[18]

To create ranges around incidence calculations, Monte Carlo simulations were used to reflect the combined variation in input parameters, including organ donor prevalence as calculated in this study, blood donor prevalence and incidence as reported in the literature, and window periods for serologic and NAT tests (Table 2). Since the variability surrounding window period inputs was unknown, triangular distributions with 50% variation were assigned to reflect unknown (and thus conservative) distribution and variance parameters. Ranges around incidence estimates were generated from 10 000 repeated calculations resulting in a 95% credible interval around the incidence estimates. All analyses were calculated with SAS 9.2 and in Crystal Ball software applications.

Results

Serologic data were submitted for 13 677 potential donors (n = 13 607 for anti-HIV and n = 13 349 for anti-HCV) (Table 1). For anti-HIV, overall adjusted prevalence was 0.21% with a credible interval (CI) of 0.15–0.29%. Prevalence was lowest for normal risk donors (n = 11 245) at 0.10% (CI = 0.06–0.16%) and highest for donors with missing risk status (n = 1182) at 1.00% (CI = 0.57–1.54%). For high risk donors (n = 1180), prevalence was 0.50% (CI = 0.21–0.86%). The overall adjusted prevalence for anti-HCV was 5.58% (CI = 5.15–6.06%). The adjusted anti-HCV prevalence was lowest for normal risk donors at 3.45% (CI = 3.10–3.85), and highest for high risk donors at 18.20% (CI = 15.74–20.91%). For donors with missing risk status, the adjusted HCV prevalence was 12.88% (CI = 10.83–15.08).

Out of all potential organ donors tested, 11.3% (n = 1538) did not have any organs recovered. Out of the 64 anti-HIV-positive donors, 58 (90.6%) did not have any organs recovered. Of the six HIV-positive donors with organs recovered, five were designated as normal risk and one was missing risk status; none were transplanted. Of 924 anti-HCV-positive potential donors, 36.0% (n = 332) did not have any organs recovered. Of the 591 anti-HCV-positive donors who did have organs recovered, 32.3% were considered high risk donors, 63.1% were considered normal risk donors and 4.6% were missing risk status.[1]

Yearly incidence estimates for HIV among all potential organ donors was approximately 61 per 100 000 person-years; for normal risk, high risk and missing risk donors the incidence was 29, 142 and 283 per 100 000 person-years, respectively. The overall incidence estimate for HCV was approximately 168 per 100 000 person-years; for normal risk, high risk and missing risk donors, incidence was 104, 547 and 387 per 100 000 person-years, respectively.

For normal risk donors, the estimated incidence of undetected HIV infection during the 22-day window period for serologic testing was approximately 1.72 per 100 000 person-years, and 0.55 per 100 000 person-years for the 7-day window period for NAT screening. For high risk donors, undetected HIV incidence per 100 000 person-years during the window periods for serologic and NAT screening were 8.54 and 2.72, respectively. The 95% credible intervals for undetected HIV infection during serologic and NAT window periods overlapped all donor risk strata (Table 2).

For normal risk donors, the estimated incidence of undetected HCV infection during the 70-day window period for serologic testing was approximately 19.91 per 100 000 person years, and 1.99 per 100 000 person-years for the 7-day window period for NAT testing. For high risk donors, undetected HCV incidence per 100 000 person-years during the window periods for serologic and NAT screening were 104.94 and 10.49, respectively. The 95% credible intervals for undetected HCV infection during serologic and NAT window periods did not overlap for any risk strata, indicating significant potential reductions conferred by NAT screening as compared to serology alone for HCV.

1Authors were not able to obtain information about whether recovered HCV-positive organs were transplanted.

Discussion

In our prevalence study of over 13 000 potential organ donors, approximately 1 in 500 were positive for anti-HIV after adjusting for false-positive serologic testing, with higher prevalence among high risk donors (1 in 200) versus normal risk donors (1 in 1000). One in 18 of all potential donors were positive for anti-HCV after adjusting for false-positive serologic testing; the prevalence among high risk donors was striking (1 in 5), and that among normal risk donors was substantial (1 in 30).

Findings suggest that organ donors are at higher risk of undetected infection by serologic screening (i.e. incident infection during the window period) compared to tissue donors. In 2004, tissue donors were reported to have a 1 in 55 000 risk of undetected HIV and 1 in 42 000 risk of undetected HCV infection by serologic screening.[7] In this study, normal risk organ donors had an estimated 1 in 60 000 risk of undetected HIV infection by serologic screening, which is similar to tissue donors; however, high and missing risk organ donors were at substantially higher risks of undetected HIV infection (1 in 12 000 and 1 in 6000, respectively). Organ donors of all risk strata had a higher risk of undetected HCV infection by serologic testing compared to tissue donors. In this study, normal risk organ donors had an estimated 1 in 5000 risk of undetected HCV infection by serologic testing, and high risk donors had a 1 in 1000 risk. For HCV, reduction in the window period for NAT screening decreased the risk by 90% of undetected infection to 1 in 50 000 for normal risk donors and 1 in 10 000 for high risk donors. Credible intervals for HCV incidence during the window period for serologic versus NAT screening did not overlap for any of the risk strata, suggesting significant risk reductions conferred by NAT screening (vs. serology alone) for HCV. Credible intervals for HIV incidence during serologic and NAT window periods do overlap for all risk strata; this is potentially a result of low HIV prevalence and incidence rates, wide variation in input parameters, and a smaller change in the window period for serology versus NAT for HIV compared with HCV (i.e. a 15 day difference vs. a 63 day difference).

The prevalence estimates of anti-HCV in high risk and normal risk donors demonstrated in this study are similar to those reported in a nation-wide analysis of donors reported to UNOS during the same time period.[9] Rates of anti-HIV in this study are higher, likely because most HIV-positive potential donors do not have organs recovered, and thus may not be reported to UNOS. This study included potential donors who had consent for testing, but who had no organs recovered likely because of their HIV status. Both this study and the nation-wide UNOS study are likely to underestimate the true prevalence of HIV among potential organ donors because HIV-positive persons are excluded from donation by law; therefore, known HIV positive persons are less likely to be consented for testing.

A nontrivial proportion (approximately 9%) of donors tested for anti-HIV and anti-HCV were missing risk status designations by OPOs. This phenomenon was not limited to one or few OPOs; 13 of the 17 participating OPOs submitted serologic testing results for donors with missing risk status. Donors with 'missing risk' status had a high prevalence of HIV (1.0%). A possible explanation is that this study included all potential donors who received serologic testing including those whose organs were not recovered due to HIV positivity. Donors no longer considered for transplantation are rarely reported to UNOS, which requires that the OPO report the risk designation, and thus OPO may not assign risk designations for these donors.

Differences in regulatory restrictions for organ donation versus blood and tissue donation may be attributed to differences in the degree of risk acceptable for the respective recipient group of each allograft. Allowing organs from high risk donors to be transplanted is one of several policies aimed at increasing the availability for life-saving organs; increasingly, organs are transplanted from donors with underlying chronic illnesses as well as donation after circulatory determination of death. Transplanting organs from these clinically suboptimal donors is presumably accepted because of the potential life years gained by the recipient or recipients.[20] In contrast, donors with behavioral risk factors are routinely excluded from the blood and tissue supply.

Decisions to recover and transplant organs are made based on several factors. Donors designated as high risk may not have their organs recovered or transplanted because of their high risk designation or because of other known medical or anatomical issues. However, because organs are in such high demand, the high risk designation may or may not dissuade a transplant center from accepting an organ. A recent survey of transplant surgeons showed that NAT screening enhanced surgeons' comfort in accepting organs from high risk donors, presumably because concerns about undetected infection were allayed.[11] Still, a recently published expert consensus concluded that there exists insufficient evidence to recommend routine NAT because the benefit may not outweigh the possibility of disqualifying organs for transplantation because of false-positive NAT results.[20] Our study suggests that adoption of NAT screening for HCV could significantly reduce the incidence of undetected infection during the window period with a particularly high yield for high risk donors; thus NAT screening could potentially improve organ acceptance from high risk donors with negative results. The question remains as to whether expanding the donor pool through enhanced acceptance of NAT-negative organs would balance or exceed organ loss from false-positive NAT. False-positive rates for NAT screening are poorly understood. False-positive NAT screening could be detrimental to the organ supply if noninfected organs are rejected. Given the concerns about false-positive NAT results, more research on the frequency and causes of false-positives is needed and protocols for NAT screening should promote maximum specificity. While this study was not designed to assess the rate of false-positive NAT screens, we do believe this phenomenon should be considered in parallel with the results from this study when making policy decisions related to NAT screening.

This study is subject to a number of limitations. Importantly, the geographic distribution of OPOs participating in this study is focused mainly on the areas of highest population density, so that results may not be generalizable nationally. Also, interpretation of the results should be predicated on the fact that most of the serologic tests used in this study (between 2004 and 2008) were third-generation tests. The introduction of more sensitive fourth-generation serologic assays would also shorten window periods and thus may be a suitable alternative to NAT screening for purposes of reducing window periods if approved by FDA. Additionally, when considering the validity of serology results, differences may exist between large reference labs and smaller production labs and may influence the relative rate of false-positive results.

The results of our study suggest that undetected infection, and potentially transmission, can occur with current testing methods, although relatively few transmission events have been reported. There may be several reasons for this discrepancy. First, it is possible that transmissions occur unnoticed because a recipient dies before the infection is detected. Under-reporting may also occur because a transplant physician is unable to identify the donor as the source of recipient infection, particularly if discovered months after the transplant. Finally, reporting of suspected disease transmissions to UNOS was not part of OPTN policy until 2005, and that policy has remained voluntary.

This study is also subject to the inherent limitations of the incidence window-period methodology in which the incidence of undetected infection among potential organ donors is estimated from incidence in the blood donor population multiplied by an organ-to-blood donor prevalence ratio. This methodology assumes that the organ-to-blood donor prevalence ratio accurately reflects the organ-to-blood donor incidence ratio. This limitation was minimized by using prevalence and incidence estimates from the same time period; all estimates used to calculate the probability of undetected infection of HIV and HCV among potential organ donors—blood donor incidence data, blood donor prevalence data and organ donor prevalence data—were collected from 2004 through 2008.

Although recent surveys indicate that NAT is feasible, as it is performed by many OPOs on some donors for at least one bloodborne pathogen, the practice is variable (11). This is of particular concern as high risk donor recovery also is highly variable, and may not be correlated with use of NAT. Because the risk of transmitting bloodborne infections through transplantation is unlikely to be completely eliminated and can be difficult to predict for each individual donor, recipients and providers should have a clear understanding of the risk and benefits through standardized informed consent at appropriate points in the transplantation listing and offering process.[21] Through ongoing collection and analysis of donor testing results as performed in our study, a better definition of transmission risk is possible, resulting in a decision process that allows for most effective use of a limited organ supply.

The Organ Procurement Organization Nucleic Acid Testing Yield Project Team

Tiffany Arrington, The Living Legacy Foundation of Maryland; Nicole Berry, LifeNet Health; James Bradley, New England Organ Bank; Benjamin Chau, California Transplant Donor Network; Claudia Chinchilla-Reyes, Mendez National Institute of Transplantation; Stephanie Cozby, LifeCenter Northwest; Wayne Dunlap, LifeCenter Northwest; A. Bradley Eisenbrey, Gift of Life Michigan; Patricia Harris, New Jersey Organ and Tissue Sharing Network; Richard Hasz, Gift of Life Donor Program; Emily Johnson, Washington Regional Transplant Community; Curt Kandra, Pacific Northwest Transplant Bank; David Marshman, LifeNet Health; Thomas Mone, OneLegacy; Helen Nelson, Golden State Donor Services; Patricia Niles, New Mexico Donor Services; Kevin O'Connor, LifeCenter Northwest; Eugene Osborne, California Transplant Donor Network; Joseph Roth, New Jersey Organ and Tissue Sharing Network; Deborah Savaria, LifeChoice Donor Services; Edwin Serna, Nevada Donor Network; Lisa Stocks, Lifesharing—A Donate Life Organization; Katrina Tanner, Gift of Life Michigan; Waheed Tajik, New York Organ Donor Network; Sharon West, Gift of Life Donor Program.

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