June 30, 2011

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


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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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.


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.



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.

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More Than Two-Thirds of Surveyed U.S. Clinicians Plan to Prescribe Incivek and Victrelis to Patients with Treatment-Naive Hepatitis C Virus Genotype 1

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/.

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Christopher Comfort, 781-993-2597