ID Advisor - Vol. 3, Issue 1 by McMahon Group

VOL. 3, ISSUE 1

EHRs Pose Challenges for HIV Clinics

CLINICAL CORNER The relationship between providers and patients is crucial for HIV care.

CLINICAL CORNER Results from the international, Phase 3, double-blind VERxVE trial.

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he data-reporting requirements for HIV clinics continue to grow. The specific demands from funding sources, particularly federal money provided through the Ryan White HIV/AIDS Treatment Extension Act of 2009, require an uncommon level of compliance.1 Clinics must implement an automated data reporting system for electronic health records (EHRs) and generate reports to comply with Ryan White funding requirements.1 “HIV care is complicated because of the growing demand for a broad array of services. Choosing an appropriate EHR system can make things easier, but a limited system can make things more difficult,” said Ann Scheck McAlearney, ScD, associate professor, College of Public Health at The Ohio State University in Columbus. Her research has shown that complex regulatory and reporting requirements, rather than simple tasks like ordering lab results, may be a key challenge

for deriving efficiency from an EHR system.2 Clinics aligned with hospitals already may have adapted to an EHR system, but even comprehensive systems may have serious limitations for HIV care. The information captured in EHR systems that are not specifically designed for HIV may be inadequate. Tasks that involve see EHRs, page 5

Psychosocial Issues Impact HIV Care

everal years ago, a patient with HIV arrived at the infectious disease program at Grady Health System in Atlanta, Georgia, with a bottle of pills covered in soot. A nurse jokingly asked, “Where are you keeping this, the fireplace?” The patient responded, “How did you guess?” Fearing stigma and discrimination, the woman was hiding her pills in order to keep her HIV status a secret. Today patients are saddled with tough decisions regarding disclosing

their infection status, sexual activity, and parenthood, among others.1 A lack of social support in dealing with these issues can lead to depression that, in turn, can lead to poor adherence to treatment.2 “Patients are much more likely to be noncompliant if they are depressed, and survival is improved by treatment,” said Glenn Treisman, MD, director, AIDS Psychiatry Service at The Johns Hopkins Hospital in Baltimore, Maryland. see PSYCHOSOCIAL, page 2

VOL. 3, ISSUE 1 • 2012

Clinical Corner

Psychosocial

Strategies that nurture effective coping between partners include communication and conflict resolution, realistic continued from page 1 appraisals of problems, redefining personal goals based on the limitations of one’s illness, and maximizing support According to Dr. Treisman, the biggest problem for within the relationship (Table).4,5 health care workers trying to help depressed patients with HIV is figuring out whether they have major depression or “Many patients feel that they can’t go on because they demoralization (sometimes called adjustment disorder). now have HIV, but they find out that life isn’t that different Major depression is caused by a structural or functional with HIV except for the pills. People say, ‘Well, I can’t have brain lesion, whereas demoralization is “Patients are much more unprotected sex now,’ and I say, ‘Neither characterized by a stage of exaggerated can I. I don’t have HIV, but that is how likely to be noncompliant you get it,’” said Dr. Treisman. grief, persistent sadness, disillusionment, and despondency that arises in response if they are depressed, and Some women say they are depressed to a difficult event in a person’s life.3 because their diagnosis has quashed survival is improved by their hopes of motherhood. “You can The prevalence of major depression treatment.” have a baby [even] if you have HIV. The and demoralization among patients with problem is people who have a very unreHIV may be as high as 50%, with signifi—Glenn Treisman, MD alistic view of the world,” Dr. Treisman cant overlap between the 2 conditions.3 said. “They say, ‘I can’t have a baby now.’ I say, ‘Yes you can, “Major depression clearly responds best to medication. but who was going to have the baby with you?’ They say, The psychological kind [of depression] doesn’t respond to ‘I don’t know.’ And I say, ‘Maybe you should work on that medication at all,” said Dr. Treisman. Demoralized patients first.’” derive the greatest benefit from supportive psychotherAccording to Dr. Holstad, care providers can help disapy, encouragement, coaching, and rehabilitation.3 Some courage avoidance coping mechanisms, such as drug patients can have both kinds of depression.3 and alcohol abuse, but recognizing them can be difficult. Anhedonia is a helpful diagnostic tool. Patients with “People are good at hiding things,” she said. “Phrase quesmajor depression have profound anhedonia, which is the tions so they are not threatening. You might say, ‘A lot inability to derive pleasure from behaviors such as sleepof our patients have difficulties with drugs such as crack ing, eating, having sex, working, engaging in hobbies, and cocaine; have you ever experienced these kinds of difficulexercising.3 “People with [demoralization] can be disties?’ instead of asking, ‘Do you use illegal drugs?’” tracted from their grief when something good happens to Motivational interviewing (MI) is a client-centered tool them, but people with major depression cannot,” said Dr. health care workers can use to spur behavior change or Treisman. maintain healthy behaviors.6 “MI helps patients see that Marcia Holstad, DSN, associate professor of nursing at Emory University in Atlanta, Georgia, and a nurse practithere is a discrepancy between what their goals in life are tioner at Grady Health System, noted that she avoids using and the way they are currently behaving,” said Dr. Holstad. the word “depression” and instead asks patients if they are She said that MI often is used to treat substance abuse, but sad. “Destigmatizing the issue of mental health treatment it can help patients with HIV understand their medicationis important,” she said. taking behaviors6 and also improves self-efficacy, another Betsy Fife, RN, PhD, a senior research scientist at Indiana major predictor of medication adherence.2 University’s School of Nursing in Indianapolis, has impleDr. Holstad uses a confidence ruler ranging from 0 (not mented and evaluated an intervention that promotes at all confident) to 10 (completely confident) with her coping strategies for people with HIV and their partners.4 patients. She asks her patients to rate how confident they are in taking their medications properly. She then Table. Coping Strategies for Patients With HIV asks them to identify their barriers to achieving a higher score. These rulers, she said, can uncover Maladaptive Coping Effective Coping issues such as housing difficulties, a stressful family Self-distraction Effective communication and conflict situation, or substance abuse. resolution among family and friends After Dr. Holstad used the confidence ruler with Behavioral Using realistic appraisals of the situation one patient who rated her confidence level as 6, disengagement and prognosis she asked the patient what it would take to increase Substance abuse Setting realistic life goals based on that score to 8. The woman then admitted to using potential disease limitations crack cocaine, which is a barrier to achieving a Denial or venting Relying on a strong social support system higher score. “Many times these psychosocial issues Adapted from references 4 and 5. are worse than the disease,” she said.

2012 • VOL. 3, ISSUE 1

Clinical Corner

Patient–Provider Relationship Is Crucial to Success

iving with HIV is a constant challenge, and providers caring for patients with the disease play a key role in helping their patients meet that challenge. The current guidelines from the US Department of Health and Human Services (DHHS) state, “Patients initiating ART [antiretroviral therapy] should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence.”1 This commitment is significant, especially given the psychological and socioeconomic difficulties facing many patients who live with HIV. “A lot of people may lose social support once they get diagnosed as a result of the continuing social stigma associated with an HIV diagnosis,” said Leonard Sowah, MB, ChB, MPH, assistant professor of medicine in the Institute of Human Virology at the University of Maryland School of Medicine in Baltimore. “That makes it so important for the provider to have a relationship that may go beyond what we consider normal patient relationships. Without that relationship, a lot of patients may have difficulties with engaging in care.” Although the treatments for HIV have improved significantly over the past few years, many people living with the disease still are not receiving ART and are not engaged in care.2 One study found up to 40% of newly diagnosed patients who were given passive referrals had not initiated HIV care within 6 months of their diagnosis. Alternatively, 78% of patients who received case management and help finding HIV clinics were in care 6 months after diagnosis.3

PSYCHOSOCIAL, continued from page 2

References 1.

Bravo P, Edwards A, Rollnick S, Elwyn G. Tough decisions faced by people living with HIV: a literature review of psychosocial problems. AIDS Rev. 2010;12(2)76-88. Dilorio C, McCarty F, DePadilla L, et al. Adherence to antiretroviral medication regimens: a test of a psychosocial model. AIDS Behav. 2009;13(1):10-22. Treisman G, Angelino A. Interrelation between psychiatric disorders and the prevention and treatment of HIV infection. Clin Infect Dis. 2007;45(suppl 4):S313-S317. Fife BL, Scott LL, Fineberg NS, et al. Promoting adaptive coping by persons with HIV. J Assoc Nurses AIDS Care. 2008;19(1):75-84. Vosvick M, Koopman C, Gore-Felton C, Thoresen C, Krumboltz J, Spiegel D. Relationship of functional quality of life to strategies for coping with the stress of living with HIV/AIDS. Psychosomatics. 2003;44(1):51-58. Dilorio C, McCarty F, Resnicow K, et al. Using motivational interviewing to promote adherence to antiretroviral medications: a randomized controlled study. AIDS Care. 2008;20(3):273-283.

“As providers, we have to be able to build trust with [patients], involve them in decisions about their health care, and be really clear about what we expect them to do,” said Mary Catherine Beach, MD, associate professor in the Division of General Internal Medicine and core faculty at the Berman Institute of Bioethics and the Welch Center for Prevention, Epidemiology, and Clinical Research at Johns Hopkins University in Baltimore. She pointed out that patients with HIV may need to make lifestyle changes, such as safer sexual practices and changes in substance use habits, as well as medication adherence. “The relationship between patients and their providers is a particularly important factor in HIV care because the see PATIENT–PROVIDER, page 4

Editorial Board Maria Eugenia Fernandez-Esquer, PhD Associate Professor of Behavioral Sciences Center for Health Promotion and Disease Prevention Research University of Texas School of Public Health University of Texas Health Sciences Center at Houston Houston, Texas Harry Lampiris, MD Associate Professor of Clinical Medicine Assistant Fellowship Director ID Fellowship Training Program University of California, San Francisco San Francisco, California Glenn Treisman, MD Professor Director, AIDS Psychiatry Service Johns Hopkins University School of Medicine Baltimore, Maryland

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ID Advisor® Focus on HIV/AIDS 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. April 2012. Sponsored by

VOL. 3, ISSUE 1 • 2012

Clinical Corner

Patient–Provider

affects racial and sexual minorities.1 “Because minorities are under-reprecontinued from page 3 sented in medicine,” she said, “there’s often racial and ethnic discordance illness is a stigmatized and serious chronic illness,” between patients and providers. said Dr. Beach. Cross-cultural communication can Patient-centered care, which is defined as underbe challenging.” standing each patient as a unique person, is the stanAlso, Dr. Beach said, “Many prodard for high-quality care.4,5 “From my experience, viders are very well intentioned, the patients who really form a relationship with but not necessarily trained in their provider do much better, and they tend to communication techniques.” get a lot more engaged in their care,” said Dr. Fortunately, both cultural disparity and lack of communicaTable. Ways To Enhance the Patient–Provider Relationship tion skills can be addressed with Barriers Solutions similar tools. “I think that really Poor reimbursement Apply for Ryan White CARE Act funding; understanding where someone Create strong support system among health care workers is coming from is a critical first Racial/ethnic discordance Engage in provider communication training; step,” she said. between patient and provider Try motivational interviewing Motivational interviewing, for Based on conversations with Mary Catherine Beach, MD, and Leonard Sowah, MB, ChB, MPH. example, which engages the patient in finding his or her own motivation for behavior change, is the standard of care Sowah. “It doesn’t have to be the physician in the team. for risk reduction, according to the Centers for Disease It can be the case manager, medical assistant, or nurse. Control and Prevention.8 Luckily, said Dr. Beach, “These There are times when the team leader has to step back and allow the person who has the better relationship with are skills that people can learn, and it’s not rocket science.” the patient to lead.” Finally, said Dr. Sowah, “I think that, as human beings, Patient-centered care has a tangible effect on mediwe don’t only live for ourselves. So for some patients, cal outcomes for people living with HIV. Patients who providing them with something outside of themselves to feel that they are seen and appreciated as individuals live for helps them to engage better.” are more likely to be fully engaged with receiving and References adhering to highly active ART, and are more likely to 1. DHHS. Guidelines for the use of antiretroviral agents in HIV-1show undetectable levels of serum HIV RNA.5 It has been infected adults and adolescents: initiating antiretroviral therapy in treatment-naive patients (updated October 14, 2011). http:// shown that one of the most important issues in patient– www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescentprovider communication is how open providers are to listreatment-guidelines/10/initiating-antiretroviral-therapy-intreatment-naive-patients Accessed March 21, 2012. tening to and learning from their patients.6 “Doctors need 2. Mutchler MG, Wagner G, Cowgill BO, McKay T, Risley B, Bogart to be skilled in getting patients to express their opinions LM. Improving HIV/AIDS care through treatment advocacy: and preferences,” said Dr. Beach. “The provider has to going beyond client education to empowerment by facilitating client-provider relationships. AIDS Care. 2011;23(1):79-90. understand how the patient views [his or her] illness and 3. Gardner LI, Metsch LR, Anderson-Mahoney P, et al. Efficacy of be able to negotiate a treatment plan based on that para brief case management intervention to link recently diagticular patient’s goals and beliefs.” nosed HIV-infected persons to care. AIDS. 2005;19(4):423-431. There are some barriers to creating a good patient– 4. Balint E. The possibilities of patient-centered medicine. J Roy provider relationship, both systemic and personal (Table). Coll Gen Pract. 1969;17(82):269-276. 5. Beach MC, Keruly J, Moore RD. Is the quality of the patient“Barrier No. 1 is the reimbursement system,” said Dr. provider relationship associated with better adherence and Sowah. He stressed the importance of a strong support health outcomes for patients with HIV? J Gen Intern Med. system, with social workers, physician assistants, and 2006;21(6):661-665. other team members. He points out that, in the current 6. Apollo A, Golub SA, Wainberg ML, Indyk D. Patient-provider relationships, HIV, and adherence: requisites for a partnership. system, unless a center has Ryan White Comprehensive Soc Work Health Care. 2006;42(3-4):209-224. AIDS Resources Emergency Act funding, it may be dif7. Saha S, Sanders DS, Korthuis PT, et al. The role of cultural ficult to make sure that all these services are fully reimdistance between patient and provider in explaining racial/ethnic disparities in HIV care. Patient Educ Couns. bursed by insurance. 2011;85(3):e278-284. Racial and ethnic disparity between providers and 8. CDC. Motivational interviewing-based HIV risk reduction. patients also may be a barrier to mutual trust.7 Dr. Beach http://www.cdc.gov/hiv/topics/research/prs/resources/factsheets/mihrr.htm. Accessed March 21, 2012. pointed out that, in many areas, HIV predominantly

2012 • VOL. 3, ISSUE 1

Guidelines Spotlight

EHRs

Medicare & Medicaid Services (CMS) offered incentive payments up to $63,750 for institutions that adopted an EHR by February 2012.6 In 2015, hospitals and providers will be penalized in their Medicare reimbursements if they do not decision support tools like documenting HIV resistance successfully implement an EHR system.6 mutations or comorbidities affecting treatment decisions are not systematically recorded in offThe demands for EHRs in HIV care “Choosing an appropriate are so unique that imposing these systhe-shelf programs.2 EHR system can make tems on top of an existing EHR may The need to gather data required for funding and compliance was identithings easier, but a limited make sense. Indeed, this is the problem faced by many clinics affiliated with fied as a major drain on clinical staff in system can make things larger institutions. AVIGA REPORTER, HIV care by Jeffrey Kwong, DNP, MPH, more difficult.” which grew out of an effort to orgaANP-BC, clinical assistant professor, nize lab results and meet the CMS EHR College of Nursing, Rutgers University, —Ann Scheck McAlearney, ScD “meaningful use” requirements, is comNewark, New Jersey. “The completion patible with several of the most widely used EHR programs of grant proposals takes up enormous time and resources. that HIV/AIDS clinics already may be running by default.5 Although more HIV clinics are using an EHR system, the effort involved in pulling data out to complete the paperThe SuccessEHS system also was designed to provide work is very time-consuming. This is a major source of fruscomprehensive information collection and processing. It tration for many centers working in HIV care,” Mr. Kwong uses a dashboard-type concept to allow access to charts, said. electronic prescribing, managing lab results, and even There are several issues inherent to current EHR systems. monitoring workflow.4 However, the potential problem For example, none of them allows patient data to readily with both of these systems is the learning curve. They may be pulled for compliance filings without additonal coding require one or more staff members willing to become an to create this function.2 Moreover, these systems may be in-house expert. “Members of the staff who can champion the system difficult even for general use. “Simple things can be probare very helpful, but there is a risk of a bottleneck if those lematic. Take gender, for example. Many programs provide individuals are overwhelmed with questions when they are 2 fields. Is the patient male or female? The transgender attempting to keep up with their normal workload,” Dr. patient who goes by a nickname, or the patient who has McAlearney advised. She indicated that there may be no no fixed address can both be challenging not just for the seamless solutions for adapting to new EHR technology, intake, but also for the reporting that is required once but the goal will be to minimize the pain. these patients need to be followed,” said Dr. McAlearney. Mr. Kwong, who was unaware of but intrigued by recent EHR systems promise to solve data management probdevelopments in EHR systems specific to HIV care that lems in medicine, and they might do so when the systems facilitate data collection for grant filing, cautioned that it work well. In her study of urban community health centers, will be important for such systems to communicate with Dr. McAlearney found that some clinical processes, such existing EHR platforms. “An EHR system that helps us comas lab orders, were simplified and expedited using an EHR pile data on HIV care for compliance but speaks to the syssystem.2 However, other processes, especially compliance tem we already have would be a huge advantage,” he said. with complex regulatory requirements, created workflow inefficiencies as users adjusted to the EHR system.2 “It typiReferences cally can be assumed that the time required to implement 1. 2011 Annual Ryan White HIV/AIDS Program Services Report and adjust to a new EHR system will be considerably lon(RSR) instruction manual. www.careacttarget.org/library/RSR_ Instruction_Manual.pdf. Accessed March 21, 2012. ger than the time predicted by the vendor,” Dr. McAlearney 2. McAlearney AS, Robbins J, Hirsch A, Jorina M, Harropo JP. added. Perceived efficiency following electronic health record implementation: an exploratory study of an urban community health center Several companies market software designed for the network. Int J Med Inform. 2010;79(12):807-816. unique demands of HIV care. e-MD claims that existing soft3. AIDS care finds success implementing electronic health record ware can be tailored to meet the needs of HIV care.3 Others, [press release]. e-MDs; August 3, 2010. http://www.e-mds.com/ news/release_archives/20100803.html. Accessed February 7, 2012. such as the SuccessEHS, AVIGA, and AVIGA REPORTER, 4. SuccessEHS: Solutions for HIV clinics. http://www.successehs.com/ are programs specifically designed for application in this images/stories/downloads/bro-solutions-for-hiv-v2.pdf. Accessed setting.4,5 Most emphasize the capability for quality assurFebruary 7, 2012. 5. AVIGA product comparison. http://www.avigaehr.com/productance reporting, such as that demanded by the Ryan White comparison. Accessed March 21, 2012. Comprehensive AIDS Resources Emergency Act.4,5 There 6. EHR incentive programs. CMS Web site. https://www.cms.gov/ also are initiatives to promote EHRs in the United States EHRIncentivePrograms/01_Overview.asp#TopOfPage. Accessed March 21, 2012. through a “carrot-and-stick” approach. The Centers for continued from page 1

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Clinical Corner

VIRAMUNE® XR™ (nevirapine) extended-release, 400 mg tablets INDICATIONS AND USAGE VIRAMUNE is indicated for use in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection. VIRAMUNE XR is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. Important Considerations: • Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, nevirapine should not be initiated in adult females with CD4+ cell counts >250 cells/mm3 or in adult males with CD4+ cell counts >400 cells/mm3 unless the benefit outweighs the risk. • The 14-day lead-in period with immediate-release VIRAMUNE 200 mg daily dosing must be strictly followed; it has been demonstrated to reduce the frequency of rash. • If rash persists beyond the 14-day lead-in period with immediate-release VIRAMUNE, do not begin dosing with VIRAMUNE XR. The lead-in dosing with 200 mg once-daily immediate-release VIRAMUNE should not be continued beyond 28 days, at which point an alternative regimen should be sought. • Adult patients already on a regimen of immediate-release VIRAMUNE twice daily can be switched to VIRAMUNE XR 400 mg once daily without the 14-day lead-in period of immediate-release VIRAMUNE. • For patients who interrupt VIRAMUNE XR dosing for more than 7 days restart the recommended lead-in dosing with immediate-release VIRAMUNE, using one 200 mg tablet daily for the first 14 days.

IMPORTANT SAFETY INFORMATION WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN REACTIONS HEPATOTOXICITY: Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with nevirapine. In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. These events are often associated with rash. Female gender and higher CD4+ cell counts at initiation of therapy place patients at increased risk; women with CD4+ cell counts >250 cells/ mm3, including pregnant women receiving nevirapine in combination with other antiretrovirals for the treatment

of HIV-1 infection, are at the greatest risk. However, hepatotoxicity associated with nevirapine use can occur in both genders, all CD4+ cell counts and at any time during treatment. Hepatic failure has also been reported in patients without HIV taking nevirapine for post-exposure prophylaxis (PEP). Use of nevirapine for occupational and non-occupational PEP is contraindicated. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue nevirapine and seek medical evaluation immediately. SKIN REACTIONS: Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine and seek medical evaluation immediately. Transaminase levels should be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. The 14-day lead-in period with immediate-release VIRAMUNE 200 mg daily dosing has been observed to decrease the incidence of rash and must be followed. MONITORING: Patients must be monitored intensively during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of these events. Do not restart nevirapine following clinical hepatitis, or transaminase elevations combined with rash or other systemic symptoms, or following severe skin rash or hypersensitivity reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment. CONTRAINDICATIONS: Nevirapine is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment or for use in occupational and non-occupational PEP. Patients taking nevirapine should not take St. John’s wort or efavirenz. Please see full Prescribing Information for additional drug to drug interactions. Immune reconstitution syndrome has been reported in patients treated with combination ARV therapy, including nevirapine. Fat redistribution or accumulation of body fat has been reported in patients receiving ARV therapy. The mechanism and long-term consequences of this are unknown. Other less common side effects include nausea, fatigue, fever, headache, vomiting, diarrhea, abdominal pain, and myalgia.

2012 • VOL. 3, ISSUE 1

Clinical Corner

The International VERxVE Trial Evaluated VIRAMUNE XR versus VIRAMUNE in ARV Treatment–naïve Adult Patients VERxVE: Trial Overview and Design The VERxVE trial is an ongoing, multinational, Phase 3, double-blind, double-dummy, parallel-group, activecontrolled trial with stratified randomization.1 It is being conducted at 175 centers in 20 countries around the world: 305 trial subjects from North America and Australia; 541 from Europe; 112 from Latin America; and 110 from Africa.2 The primary objective of this trial is to evaluate the efficacy of VIRAMUNE XR 400 mg once daily in comparison with VIRAMUNE 200 mg twice daily after 48 weeks of treatment. The patients are antiretroviral treatment-naïve men and women with CD4+ cell counts >50 to <400 cells/mm3 and >50 to <250 cells/mm3, respectively, and an HIV-1 viral load (VL) of ≥1000 copies/mL. The CD4+ cell count criteria for this population were chosen specifically to reduce the risk of hepatotoxicity for men and women with CD4+ cell counts >400 cells/mm3 and >250 cells/mm3, respectively. Stratification was by baseline HIV-1 VL (defined as the maximum of screening VL or Day 0 viral load): ≤100,000 copies/mL or ≥100,000 copies/mL. This was a noninferiority trial in which –10% was defined as the lower boundary of the 95% confidence interval (CI) of the difference in virologic response proportions between the VIRAMUNE and VIRAMUNE XR groups.2 Following genotypic confirmation of susceptible HIV-1 and other eligibility criteria, treatment-naïve adult patients received a lead-in dose of VIRAMUNE 200 mg once daily for 14 days (N=1068). After this open-label lead-in period, patients were randomized in a 1:1 ratio to either VIRAMUNE XR 400 mg once daily or VIRAMUNE 200 mg twice daily; both treatment groups also received Truvada® once daily.1 A double-dummy design was used to maintain blinding if adult patients tolerated the lead-in treatment period.2 The duration of treatment was 48 weeks for the primary endpoint within each stratum,1 with an extension to 144 weeks.2 The extension period began after each adult patient had completed the Week 48 visit for the purpose of collecting long-term safety and efficacy data.1

VERxVE: Outcome Evaluations Primary Endpoint The primary endpoint of this trial was sustained virologic response at Week 48. A virologic response was defined as 2 consecutive measurements of VL <50 copies/mL, at least 2 weeks apart. A sustained virologic response had no virologic rebound or change of ARV

therapy through Week 48. The time window of Week 48 was defined as 48±4 weeks from Day 0 (the day a patient started treatment).2 A virologic rebound was defined by 2 consecutive VL measurements ≥50 copies/mL, at least 2 weeks apart, after a virologic response. If there was an unconfirmed change of VL status (rebound or response) at Week 48, then another measurement at least 2 weeks later was necessary to confirm whether virologic rebound or response had occurred.2

Secondary Endpoints A few of the secondary efficacy endpoints included mean change in CD4+ cell count at Week 48, treatmentemergent resistance, and time to new AIDS or AIDSrelated progression event or death.2 Other secondary safety endpoints included adverse events and serious adverse events (including AIDS-defining events), occurrence of rashes and hepatic events, occurrence of elevations in laboratory measurements by Division of AIDS (DAIDS) Grade, and occurrence of discontinuations due to adverse events.2

VERxVE: Efficacy Data Virologic Success and CD4+ Cell Count Changes The primary efficacy endpoint was sustained virologic response at Week 48 using LLOQ (lower limit of quantification) = 50 copies/mL.2 Using SNAPSHOT analysis, a virologic success was defined as a patient with a VL <50 copies/mL in the Week 48±4 window (using the last measurement if multiple measurements were taken in the window). Based on the SNAPSHOT analysis, at Week 48, 75% of VIRAMUNE and 80% of VIRAMUNE XR patients were Virologic Successes (Figure 1, page 8).1 The results from all secondary analyses of the primary endpoint show the difference in sustained virologic response proportion between VIRAMUNE XR and VIRAMUNE was 4.9% (95% CI, -0.2%, 10.1%). The baseline HIV-1 viral load ≤100,000 copies/mL stratum had a higher response proportion than the >100,000 copies/ mL stratum and this result was observed for both treatment groups.1,2 There appeared to be no relationship between baseline CD4+ cell count and the response proportion (Table, page 8).1,2 The SNAPSHOT approach also was used to analyze virologic failure. Patients who changed optimized background therapy (OBT) to new class or changed OBT not see VERXVE, page 8

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Clinical Corner

Figure 1. Virologic Success at Week 481,2

VERxVE Patients With Undetectable Viral Load at Week 48 Virologic Successa,b (HIV-1 RNA <50 copies/mL), %

continued from page 7

VIRAMUNE

120

VIRAMUNE XR

100 80

60 40 20 0

Total

100,000

100,000 Baseline VL

a A patient with a VL<50 copies/mL in the Week 48±4 window (using the last VL measurement if multiple measurements were taken in the window) was defined as a Virologic Success.1,2 b

Adjusted for baseline HIV-1 VL stratum.

Table. Mean CD4+ Cell Count and Changes at Week 481,2 VIRAMUNE Mean CD4+ Count at Baseline (cells/mm 3 ) 3 a

Mean Change in CD4+ Count (cells/mm )

VIRAMUNE XR

228

230

+191

+206

Adjusted for baseline HIV-1 VL stratum.

permitted per protocol or due to lack of efficacy prior to Week 48, patients who discontinued prior to Week 48 for lack or loss of efficacy, and patients with HIV RNA >50 copies/mL in the Week 48 window were considered a virologic failure.2 Using SNAPSHOT analysis, the virologic failure proportion was 13% in the VIRAMUNE group and 11% in the VIRAMUNE XR group (Figure 2).1

VERxVE: Data Selected Adverse Events The safety data include all adult patient visits up to the last patient’s completion of the 48-week primary endpoint in the trial (mean observation period, 61 weeks).1 After the lead-in period, the incidence of any hepatic event was 9% in the VIRAMUNE group and 6% in the VIRAMUNE XR group. The incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3% in the VIRAMUNE group and 2% in the VIRAMUNE XR group. The incidence of Grade 3 or 4 ALT/AST elevations was 7% in the VIRAMUNE group and 6% in the VIRAMUNE XR group (Figure 3).1

Overall, there was a similar incidence of symptomatic hepatic events among men and women enrolled in VERxVE.1

Selected Adverse Reactions Adverse reactions of at least moderate intensity (Grade 2 or above) and considered to be related to treatment by the investigator in at least 2% of treatment-naïve patients receiving either VIRAMUNE or VIRAMUNE XR after randomization were rash and clinical hepatitis. Severe or life-threatening rash considered to be related to nevirapine treatment occurred in 1% of patients during the lead-in phase with VIRAMUNE, and in 1% in each treatment group during the randomization phase. In addition, 5 cases of Stevens-Johnson syndrome were reported in the trial, all of which occurred within the first 30 days of treatment (Figure 4, page 10).1

Pharmacokinetic Data VIRAMUNE XR is absorbed throughout the the gastrointestinal tract. The extended-release 400 mg oncedaily formulation was developed to provide consistent drug levels over 24 hours (Figure 5, page 10). The

2012 â&#x20AC;˘ VOL. 3, ISSUE 1

Clinical Corner

Figure 2. Virologic Failure Rates1 Patients With Virologic Failure at Week 48 50

VIRAMUNE XR

VIRAMUNE

Patients, %

SNAPSHOT A nalysisa

Total

Includes patients who changed optimized background therapy (OBT) to new class or changed OBT not permitted per protocol or due to lack of efficacy prior to Week 48, patients who discontinued prior to Week 48 for lack or loss of efficacy, and patients with HIV RNA >50 copies/mL in the Week 48 window.

Figure 3. Selected Adverse Events1 Selected Adverse Events During the Randomization (Post Lead-in) Phase 50

Patients, %

VIRAMUNE (n=506)

VIRAMUNE XR (n=505)

7 3

A ny Hepatic Event

Symptomatic Hepatic Eventsa

Grade 3 or 4 A LT/ A ST Elevation

Symptomatic hepatic events included anorexia, jaundice, and vomiting.

bioavailability of VIRAMUNE and VIRAMUNE XR was tested under fasted and fed conditions with VIRAMUNE showing 100% bioavailability in both settings. The bioavailability of VIRAMUNE XR was 80% under fasted conditions and 94% under fed conditions. The difference in the bioavailability of nevirapine when VIRAMUNE XR was dosed under fasted and fed conditions is not considered clinically relevant.1

Dosing and Administration ARV/VIRAMUNE-naĂŻve Adult Patients Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, VIRAMUNE should not be initiated in adult females with CD4+ cell counts >250 cells/mm3 or in adult males with

CD4+ cell counts >400 cells/mm3, unless the benefit outweighs the risk.1 Adult patients must initiate therapy with one 200 mg tablet of VIRAMUNE daily for the first 14 days in combination with other ARV agents, followed by one 400 mg tablet of VIRAMUNE XR once daily in combination with other ARV agents. The 14-day lead-in period with VIRAMUNE 200 mg daily dosing has been demonstrated to reduce the frequency of rash. If rash persists beyond the 14-day lead-in period with VIRAMUNE, do not begin dosing with VIRAMUNE XR. The lead-in dosing with 200 mg once-daily VIRAMUNE should not be continued beyond 28 days, at which point an alternative regimen should be sought. If dosing is interrupted for greater than 7 days, restart the 14-day lead-in dosing.1 see VERXVE, page 10

VOL. 3, ISSUE 1 • 2011

Clinical Corner

VERxVE

VIRAMUNE-experienced Adult Patients

continued from page 9

Figure 4. Selected Adverse Reactions1 Selected Adverse Reactions of at Least Moderate Intensity (Grade 2 or above) in 2% of Patients 1,a,b

Patients,%

VIRAMUNE (n=506)

VIRAMUNE X R (n=505)

Clinical Hepatitis d

Rash c

Includes adverse drug reactions considered by the investigator to be at least possibly, probably, or definitely related to the drug.

Mean observation period was 61 weeks.

Rash includes terms rash, rash maculo-papular, erythema nodosum, rash erythematous, rash papular, skin reaction, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), and allergic dermatitis.

Clinical hepatitis includes terms hepatitis, hepatotoxicity, hepatitis acute, liver disorder, hepatitis toxic, hepatic failure, and jaundice.

Figure 5. VIRAMUNE XR (400 mg) Delivered Consistent Drug Levels Over 24 Hours

Nevirapine Plasma Concentrations (μg/mL)

200 mg VIRAMUNE (n=25) 400 mg VIRAMUNE XR (n=24) a

Adult patients already on a regimen of VIRAMUNE 200 mg twice daily in combination with other antiretroviral agents can be switched to VIRAMUNE XR 400 mg once daily in combination with other antiretroviral agents without the 14-day lead-in period of once-daily VIRAMUNE 200 mg and without the CD4+ cell count restrictions.1

VERxVE: Clinical Data Summary1 Among 1,011 patients randomized and treated, the Virologic Success at Week 48 was 75% for VIRAMUNE and 80% for VIRAMUNE XR. The mean CD4+ cell count increase from baseline at Week 48 was 191 cells/mm3 for VIRAMUNE and 206 cells/mm3 for VIRAMUNE XR. Adverse reactions of at least moderate intensity (Grade 2 or above) in ≥2% of patients were: • Rash: 3% for both VIRAMUNE and VIRAMUNE XR • Clinical hepatitis: 3% for VIRAMUNE; 2% for VIRAMUNE XR

VIRAMUNE XR: Overall Summary1,2 In the VERxVE trial, sustained virologic response, based on the SNAPSHOT analysis at Week 48 was 80% for VIRAMUNE XR and 75% for VIRAMUNE.1 Adult patients already on a regimen of VIRAMUNE 200 mg twice daily can be switched to one 400 mg tablet of VIRAMUNE XR once daily in combination with other ARV agents1: • Without the 14-day lead-in period of oncedaily VIRAMUNE 200 mg • Without CD4+ cell count restrictions • VIRAMUNE XR tablets can be taken with or without food1 • VIRAMUNE XR tablets must be swallowed whole and must not be chewed, crushed, or divided1

References 1. Viramune® XR™ (nevirapine) extended-release tablets. Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc.; 2011. 2. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc. Time (Hours)

a At steady state, VIRAMUNE XR 400 mg once daily delivered consistent drug plasma levels over 24 hours allowing for once-daily dosing.

Please see Important Safety Information on page 6, and enclosed full Prescribing Information, including Boxed Warning, for VIRAMUNE® XR™ (nevirapine) extendedrelease, 400 mg tablets.

2012 • VOL. 3, ISSUE 1

Practice Profile

Spotlight on Hopkins AIDS Care Program The Moore Clinic is the outpatient unit supervised by the Hopkins ID Advisor: Focus on HIV/AIDS presents the Practice Profile AIDS Service. The clinic currently comprises 7 major speseries. In each segment, we spotlight an exemplary HIV/ AIDS treatment center or practice. In this issue, we highlight cialty services: gastroenterology, neurology, psychiatry, the multidisciplinary Hopkins HIV/AIDS Care Program in gynecology, obstetrics, ophthalmology, and dermatolBaltimore, Maryland. ogy.1 In responding to the needs of their patients, said Ms. Keruly, “We co-located services very early on, and the specialties change over time based on need. There was a The Hopkins AIDS Care Program began in January 1984 group of clinicians/scientists that had an interest in this with the opening of the Moore Clinic for patients with HIV disease, so we were able to amass a group to take care infection. It has since developed into a full-service care of very complex patients, under the leadership of John network.1 “The AIDS care program was originally estabBartlett, MD.” lished to meet the need for Stephen Berry, MD, who graduated from primary care services for peo“[John Bartlett, MD] is the fellowship program in 2010 and recentple who didn’t have medical one of the world’s forely joined the faculty as assistant professor insurance,” said Jeanne Keruly, of medicine in the Division of Infectious MS, CRNP, assistant professor most infectious disease Diseases, was attracted to the ID fellowof medicine and director of researchers but didn’t ship in part because of Dr. Bartlett’s repuRyan White Adult Services forget his connection to tation. Dr. Bartlett was inspiring, Dr. Berry in the Division of Infectious the clinical world.” said, because of his combined abilities. Diseases at the Johns Hopkins “He is one of the world’s foremost infecUniversity School of Medicine —Stephen Berry, MD tious disease researchers but didn’t forget in Baltimore. “It has grown his connection to the clinical world.” over the years to meet the For Dr. Berry, the Moore Clinic database is a big part of changing needs of the population.” The AIDS Service curthe reason he ultimately chose to stay at Johns Hopkins. rently comprises 6 arms: an inpatient unit, a social work The database was established in 1989 and collects a program, 3 outpatient clinical programs, several specialty wealth of information about resource utilization.1 “For my services located in the outpatient clinics, a large clinical research program, and a longstanding observational research interest in the cost-effectiveness of modern HIV study of patients in care—the HIV Clinical Cohort datacare,” said Dr. Berry, “it’s wonderful because it’s one of base also known as the Moore Clinic database. the most comprehensive databases out there.” Because “The 1980s and 1990s were a period of big change all patients were asked for consent from the beginning of for ID [infectious disease] training because with HIV, we the database, he noted, “we can study everything about had a whole new fund of knowledge. There was a lot of a case; not just CD4 counts or medications, but insurance research happening in the course of clinical care,” said status and other medical conditions.” Stuart Ray, MD, professor of medicine and oncology, and Dr. Berry finds the culture of the AIDS Service inspiring director of the Infectious Diseases Fellowship training as well, and believes it stems in part from the combinaprogram in the Division of Infectious Diseases at Johns tion of serious clinical care and research fostered by Dr. Hopkins University School of Medicine. “HIV was clearly a Bartlett and his colleagues. “I would say that it’s a unique condition where it wasn’t enough to have a doctor,” said situation,” said Dr. Berry, “where we are expected to learn Dr. Ray. “You needed a big multidisciplinary team to manfrom everything we do, clinically. One place where this culage all the challenges that HIV presented. We developed ture is really evident is in our weekly conference.” During a group of staff that became the heart of that service.” this conference, fellows present the faculty with the most According to Dr. Ray, ID fellows who rotate through challenging cases of the past week and the faculty are the AIDS Service spend their first 3 to 4 months on the called on to come up with a differential diagnosis. The general ID consult service, 2 months at the Johns Hopkins fellow who presents the case is then expected to give an Bayview Medical Center on general consult, 2 months on answer and provide literature on an interesting component the Transplant ID Consult service, and 2 to 3 months on of the case. the inpatient Polk Unit HIV service. Fellows rotate through “This kind of conference is common across all ID felthe ID clinic, and some of these rotations are located in the lowships, but what’s different is that we put the faculty Moore Clinic for HIV Care. In the second year, fellows also members on the spot rather than putting fellows on the complete a 1-year HIV Continuity Clinic at the Moore Clinic. see JOHNS HOPKINS, page 12

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HIV179617PROF

ID Advisor Focus on HIV/AIDS provides support and information for the next generation of ID/HIV specialists.

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Johns Hopkins continued from page 11

spot,” said Dr. Berry. “To me this epitomizes the fact that everybody here is trying to learn from the medical conditions and patients we see.” Ms. Keruly also emphasized these weekly conferences as a cornerstone of the fellowship program. “The weekly clinical conference is attended by a lot of our faculty and clinical staff,” said Ms. Keruly, “and it’s incredibly useful.” The Johns Hopkins AIDS Service, said Kelly Gebo, MD, MPH, associate professor of medicine in the Division of Infectious Diseases, associate professor of epidemiology at Johns Hopkins Bloomberg School of Public Health, and director of Undergraduate Public Health Studies at Johns Hopkins University, is “a unique opportunity to deliver HIV care to a very needy group of patients in an ideal setting, where you have other support services present.” For example, social workers help educate the fellows about resources that patients may need, and how to access them. “I think that’s particularly important for trainees,” she said. Dr. Gebo finds working as a faculty member satisfying because, she said, “I like seeing providers going from novices at HIV care to completely savvy about it in the end. That’s really rewarding, to feel that we’ve made progress in teaching them that in a relatively short period of time.” QR Code for ID Advisor Use your smartphone’s camera and any QR decoding software to instantly access related materials and/or Web sites.

“HIV has been the model for dealing with issues of complex care and polypharmacy, and we can’t manage that alone,” said Dr. Ray. “The personnel at the clinic don’t come and go the way that the attendings and the fellows do—we have people who have been here for 20 years. It provides continuity and serves as a model for multidisciplinary team interaction and research.” Besides the clinic time, most of the second- and thirdyear fellowships are spent conducting research. “Most of our fellows get some kind of formal training in research,” said Dr. Ray. “Some of them spend their time primarily in the lab.” This is facilitated by the division’s funding structure, which funds training for fellows in their second and third years. Ms. Keruly points out that part of the reason the multidisciplinary team has worked so well is that the clinicianscientists on the team have an interest in studying the components of the disease. “This is not only clinical care; they have a research interest,” she said. “All the parts— the clinician-scientist, the case manager/social worker— give the fellows a really good picture of what they would be dealing with as doctors in HIV care.” “Finding where the need and your passion intersect is when you know you’ve found the right place. For a lot of [physicians], HIV provides that,” said Dr. Ray, “and we certainly foster that search.”

Reference 1.

The Body: Johns Hopkins AIDS Service. http://www.thebody. com/content/art12096.html. Accessed March 21, 2012.