Reducing the Diagnostic Window for Acute HIV

Reducing the Diagnostic Window for Acute HIV ARCHITECT HIV Ag/Ab Combo See intended use and important safety information on the next page. The Clinical and Economic Value of Early Detection Using 4 th Generation HIV Combo Tests Put science on your side.

Intended Use and Important Safety Information For In Vitro Diagnostic Use Only Intended Use: The ARCHITECT HIV Ag/Ab Combo assay is a chemiluminescent microparticle immunoassay (CMIA) for the simultaneous qualitative detection of human immunodeficiency virus (HIV) p24 antigen and antibodies to HIV type 1 (HIV 1 group M and group O) and/or type 2 (HIV-2) in human serum and plasma (EDTA and heparin). The ARCHITECT HIV Ag/Ab Combo assay is intended to be used as an aid in the diagnosis of HIV-1/HIV-2 infection, including acute or primary HIV-1 infection. The assay may also be used as an aid in the diagnosis of HIV- 1/HIV-2 infection in pediatric subjects (i.e., children as young as two years of age) and in pregnant women. An ARCHITECT HIV Ag/Ab Combo reactive result does not distinguish between the detection of HIV-1 p24 antigen, HIV-1 antibody, or HIV-2 antibody. The ARCHITECT HIV Ag/Ab Combo assay is not intended for use in screening blood or plasma donors. The effectiveness of ARCHITECT HIV Ag/ Ab Combo for use in screening blood or plasma donors has not been established. However, this assay can be used as a blood donor screening assay in urgent situations where traditional licensed blood donor screening tests are unavailable or their use is impractical. Important Safety Information: United States Federal Law restricts this device to sale and distribution by or on the order of a physician, or to a clinical laboratory; and use is restricted to by or on the order of a physician. Package insert instructions must be carefully followed. Reliability of assay results cannot be guaranteed if there are any deviations from the instructions in the package insert. This product contains sodium azide. Contact with acids liberates very toxic gas. This material and its container must be disposed of in a safe way.

HIV: A Shared Responsibility An estimated 1.2 million persons in the U.S. are currently living with HIV infection, and 50,000 new cases occur each year. 1 Additionally, more than 15,000 people die from AIDS annually. 2 Yet despite the continuing epidemic, too many Americans no longer view HIV as a serious concern. 3 In the United Kingdom, a public health official says HIV/AIDS has become just another treatable disease, it s dropped off the radar. 4 EARLIER THERAPY HIV screening has gone by the wayside, even though the CDC says every American deserves to be tested, said Dr. Donna Sweet of the University of Kansas School of Medicine Wichita. Too many physicians still think that testing is onerous administratively or that their patients aren t likely to have HIV, neither of which is true. The fact is none of us can afford to be complacent about HIV. The CDC says it well: HIV TRANSMISSIONS Each new generation needs to be reminded of the still-serious nature of HIV and the importance of prevention. Three decades after CDC reported the first cases of AIDS, the sense of national crisis may have waned but our resolve cannot. 5 HIV/AIDS exacts a terrible toll on patients health and costs the U.S. healthcare system billions of dollars. 6 Fortunately, as this briefing will discuss, one of the keys to easing this burden has long been common knowledge: Early HIV detection can not only improve patient outcomes but also significantly reduce the incidence of HIV transmission. Recent advances in HIV testing offer a potentially better and more cost-effective option for detecting newly infected HIV patients. The 4 th generation HIV test is recommended as the initial test in the CDC s recently introduced testing guidelines. 7 It has become a standard of care in numerous countries because it enables healthcare providers to diagnose highly infectious acute HIV patients who represent the greatest risk of transmitting HIV to others. 8 Echoing the theme of a recent World AIDS Day ( Shared Responsibility: Strengthening Results for an AIDS-Free Generation ), this briefing will examine the shared responsibilities of hospitals, physicians, laboratories and public health professionals in preventing the spread of HIV. It will cover the importance of routine HIV screening; how early diagnosis and treatment greatly improve patient outcomes; and why 4 th generation testing is needed to help close the diagnostic window for acute HIV. It also will discuss the CDC s new recommended testing algorithms incorporating 4 th generation HIV testing and their cost benefits to providers and the health system.

The CDC Recommends HIV Screening for Everyone Healthcare providers play a pivotal role in combating complacency about the HIV epidemic. They should, of course, continue to educate the public about HIV and its high-risk activities such as unprotected sex, needle sharing and sex with multiple partners. Everyone also needs to know that HIV doesn t discriminate -- it affects men, women and children of all races, ages, and sexual orientations. 9 Most people may be surprised to learn that an estimated 1 in 4 of all new HIV cases in 2010 were heterosexuals. 10 1 in 8 PEOPLE INFECTED WITH HIV DON T KNOW IT But for primary care, ED and other physicians/ public health professionals, probably the best thing they can do every day is to always consider testing for almost every patient. Early detection of HIV greatly improves outcomes and may be one of the most effective ways to slow the spread of HIV. That is why: HIV-infected patients who are not tested or whose antibody-only test results do not show HIV represent missed opportunities to initiate early therapy and prevent additional infections. the CDC recommends HIV screening for everyone in all health care settings. 11 the U.S. Preventive Services Task Force (USPSTF) recommends that clinicians screen for HIV infection in adolescents and adults ages 15-65. 12 In an Executive Order, President Obama noted the importance of prompt HIV diagnosis. 13 The science shows that only doing risk-based testing is not effective, said Carl Schmid, Deputy Executive Director of the AIDS Institute. There are more than 200,000 people who are living with HIV and don t know it. To find them and initiate treatment, we must implement routine HIV testing. According to the USPSTF, convincing evidence shows that identification and treatment of HIV infection is associated with a markedly reduced risk for progression to AIDS, AIDS-related events, and death in individuals with immunologically advanced disease. 14 HIV testing is the linchpin for prevention and treatment. For people who test HIV-positive, diagnosis opens the door to life-saving treatment, which also reduces the risk of transmitting HIV to others. 19 Dr. Jonathan Mermin, Director, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention Prompt diagnosis can lead to early treatment, which not only results in significantly better outcomes but also helps prevent those unaware that they have HIV from infecting others. Consider: one in 8 people with HIV doesn't know it. 15 54% of new sexually transmitted HIV infections are by people unaware they have HIV. 16 An NIH-sponsored HIV study found that HIV transmission can be reduced by 96 percent with earlier therapy. 17 Simply informing people that they are HIV-positive leads them to reduce their risk behavior by 68 percent, says Dr. Bernard Branson, the CDC s associate director for laboratory diagnostics, Division of HIV/AIDS Prevention. So that a person who knows they re infected is 3.5 times less likely to transmit HIV than a person who is infected and doesn t know it. 18

Acute HIV: Underdiagnosed and Highly Infectious A positive development in the fight against HIV has been recent Improvements in HIV testing. As President Obama noted in his Executive Order, Because of recent advances in HIV testing technology, HIV can be detected sooner and more rapidly than ever before. 20 Yet too often clinicians do not identify most patients who have acute HIV, which often presents as a non-specific viral illness within 2 to 6 weeks of infection. 21 22, 23 During this time, HIV is in its most infectious phase and is often underdiagnosed for two reasons: NON-SPECIFIC VIRAL ILLNESS? Since patients with acute HIV can appear to have the flu or mononucleosis, 24 physicians often do not test them for HIV. And even if physicians do test for HIV, traditional antibody-only diagnostic tests may not detect early acute HIV. 25 ANTIGEN ANTIBODIES In a presentation on HIV testing and treatment, Dr. Branson cited studies that showed the risk of sexual transmission is about 30-50 times higher during acute phase than during the chronic stage of infection. If we miss people with acute infection, test and treat is not going to work, said Dr. Branson. We re going to be closing the barn door after the horse is out in terms of infectiousness. 26 The HIV 4 th generation combo test detects acute infection during the early hard-to-detect phase of HIV. COMMON SIGNS AND SYMPTOMS OF ACUTE HIV Fever 86 Lethargy 74 Myalgias Rash Headache 55 57 59 Pharyngitis Adenopathy 44 52 Study of 160 patients with primary HIV infection in 3 countries % of patients Reference: Vanhems P et al. AIDS 2000; 14:0375-0381.

The Window Period and Value of 4 th Generation Combo Testing The purpose of all HIV tests is to detect biomarkers (antibodies and antigens) that indicate the virus s presence. The interval of time after infection but before HIV markers can be detected is called the window period, which varies depending on the type of test, the host responses and the viral characteristics. In 2010, Abbott introduced the ARCHITECT HIV Ag/Ab Combo assay in the U.S., a 4 th generation combination test that detects both antibodies and the p24 antigen, which can appear as early as two weeks after infection. 31 This [FDA-approved] advanced 4 th generation HIV test (also known as a combo test ) can detect HIV up to 20 days earlier than traditional antibody-only HIV tests. 32 CHOOSING A DIAGNOSTIC HIV ASSAY Acute retroviral symptoms HIV RNA/p24 antigen viral load CD4 Genital HIV RNA viral shedding HIV Abs RNA test 4 th gen Ag/Ab combo test 3 rd gen Ab-only test For example, with commonly used 3 rd generation HIV tests, the window can be 3 to 4 weeks, since that s how long it can take after infection for antibodies to be detectable. 27 At the other end of the spectrum, viral RNA can be detected within the first two weeks after infection. 28 However, PCR for HIV-1 RNA is too expensive and labor-intensive for routine diagnostic screening of 29, 30 single serum specimens. 2 7 14 3 4 5 Days Weeks Adapted from: Marquez, MLO February 2008. HIV Testing: An Update With confidence we can say that third generation antibody testing alone would miss anywhere between 10%-30% of acute HIV infections depending on the setting, said Peter Leone, M.D., professor of medicine, University of North Carolina at Chapel Hill and Medical Director for STD and HIV Prevention and Control for the North Carolina Department of Health and Human Services. Even in low prevalence settings, we re finding that 3%-4% of those identified with HIV are in the acute phase and that percentage is much higher in MSM populations. You really need antibody and antigen testing if you re going to close this window to a reasonable time. Third generation antibody testing alone will miss about 10% to 30% of acute HIV infections. With the 4 th generation testing we will pick up about 90% of these individuals. Peter Leone, M.D., professor of medicine, University of North Carolina at Chapel Hill Several recent studies support this contention. Avera McKennan Hospital & University Health Center, a 545-bed tertiary hospital in Sioux Falls, SD, reportedly was the first hospital in the U.S. to use the 4 th generation combo test. In its first seven months of testing, it performed 3,533 HIV combo assays and identified four new infections. Three of the four were acute HIV cases, which would have been missed completely using conventional testing. 33 In Arizona, the ED at Maricopa Integrated Health Systems adopted routine, optout HIV screening for all adult ED patients (aged 18-64 years) who had phlebotomy for other reasons using the ARCHITECT HIV Ag/Ab Combo assay. From July 2011 through February 2013, the screenings detected HIV in 37 patients, and of those, 12 had acute HIV infections that likely would have been missed by an antibodyonly test. 34 As the CDC Mortality and Morbidity Weekly Report noted, this finding suggests, Acute HIV infection in persons who seek care for its nonspecific symptoms in EDs and other urgent-care venues might go undiagnosed unless HIV screening is conducted with 4 th generation HIV tests. 35

Updated CDC HIV Testing Algorithm Recommends 4 th Generation Testing As previously noted, the importance of early detection and therapy and of not missing the chance to identify patients with acute HIV cannot be overestimated. To reiterate: Studies show that 50%-90% of persons with acute HIV infection develop symptoms that prompt them to seek medical care. 36 If a physician orders an HIV test but it s done with a 3 rd generation assay that only detects antibodies, the test results may be negative, and the person may not get tested again for months or years. HIV is most infectious during this acute phase. Individuals who do not know they have HIV will not receive treatment or modify their behaviors; 54% of new sexually transmitted HIV infections are by people unaware they have HIV. 37 Yet despite advances in technology, many hospitals and public health agencies are still using recommended HIV testing algorithms (protocols for decisionmaking) that are more than 25 years old. In 2012, the Clinical and Laboratory Standards Institute (CLSI) published a new set of HIV testing algorithms. 38 Similar guidelines that call for the use of 4 th generation testing also are in the CDC s 2014 recommendations. 39 Recommended HIV Laboratory Diagnostic Testing Algorithm for Serum or Plasma Specimens HIV-1 (+) HIV-2 (-) HIV-1 antibodies detected HIV-1/2 antigen/antibody combination immunoassay HIV-1/HIV-2 differentiation immunoassay HIV-1 (-) HIV-2 (+) HIV-2 antibodies detected (+) indicates reactive test result (-) indicates non-reactive test result NAT: nucleic acid test (+) (-) HIV-1 (+) HIV-2 (+) HIV antibodies detected Negative for HIV-1 and HIV-2 antibodies and p24 Ag HIV-1 (-) or indeterminate HIV-2 (-) HIV-1 NAT (+) Acute HIV-1 infection HIV-1 NAT HIV-1 NAT (-) Negative for HIV-1 The first and most noteworthy of these algorithms calls for initial use of an antigen-antibody combination assay, that is, a fourth-generation test, followed by an HIV-1/HIV-2 differentiation assay as a second, supplemental test. The first point in the CDC s new recommended testing algorithm explicitly states: Laboratories should conduct initial testing for HIV with an FDA-approved antigen/antibody combination immunoassay... 40 Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. Available at http://stacks.cdc.gov/view/cdc/23447. Published June 27, 2014. For some, such a recommendation was long overdue. The use of 4 th generation testing will allow us to catch up with Botswana, said the CDC s Dr. Branson, referring to the fact that 4 th generation tests are a standard of care in this African country. 41

Public Health Agencies Take the Lead Increased Sensitivity Earlier Confirmation 89.1% Positive Samples UP TO 20 DAYS EARLIER S M T W T F S 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 HIV Combo detected approximately 89% of infected individuals who had been missed by an initial antibody screening test. (n=64) Reference: Pandori et al, J Clin Microbiol, 2009 August; 47(8): 2639-2642 Public health agencies have adopted this recommended algorithm in many states, including New York, North Carolina, Florida, Michigan and Georgia. An APHL survey of 60 laboratories in 2012 found that 15% were using an Abbott ARCHITECT HIV Ag/Ab Combo 4 th generation immunoassay as the initial test in their HIV algorithm. 42 Berry Bennett, the Retrovirology Section Chief of Florida s Bureau of Public Health Laboratories and the past chair of the 2012 HIV Diagnostics Conference Planning Committee, implemented the new HIV Diagnostic Algorithm for use in Florida s public health sector in April 2012. Most significantly, two Florida Public Health Laboratories, Jacksonville and Miami, have detected 18 cases of acute HIV (through 2013) that would have been missed had they not been using Abbott s ARCHITECT HIV Ag/Ab Combo test. Our goal was to implement HIV Combo 4 th generation screening for as many public health clients as possible without adversely impacting our budget, said Bennett. We re detecting about one acute HIV infection per 9,000 screens, but the ratio is dropping as more Florida public health professionals become aware of the need for this type of testing, especially for patients with recent risk factors and non-specific flu-like symptoms. Florida s public health laboratories also use the algorithm to confirm all HIV-1 preliminary positive rapid tests performed at point-of-care (POC) statewide. Bennett notes, however, that the state performs approximately 200,000 POC rapid tests per year, which is why it is so important for health professionals to understand the limits of sensitivity or the window periods of these rapid tests and to draw blood if they suspect a patient may have an acute HIV infection. Although a new rapid test can now detect both HIV-1 antigen and HIV-2 antibodies, Bennett continues to use Abbott s ARCHITECT HIV Ag/Ab Combo and supplemental tests to confirm all preliminary positive results from these rapid tests. At present, data support laboratory-based 4 th generation screening tests are more sensitive than POC tests and consequently have a shorter window period, he says. Interest in routine screening for acute infection has led select centers to use the HIV Ag/Ab test as the primary HIV screening assay. 43 National Institutes of Health, Guidelines for the Use of Antiretroviral Agents in HIV-1- Infected Adults and Adolescents

Get it Right the First Time: The High Costs of False Negatives For many chronic progressive diseases, prevention and initiating treatment as early as possible can help achieve better outcomes and lower costs. Early HIV diagnosis may lead to earlier treatment and also help reduce infection rates due to potential behavior modifications made by patients aware of their HIV status. 44 When a diagnostic test comes back negative for someone who has HIV, it can result in adverse health and cost implications. HIV Combo Test It is important that appropriate treatment for HIV be provided to patients as early as possible. When the patient s virus is not under control, the cost of treating HIV is higher, primarily due to the need for more medications, hospitalizations and potentially higher readmission rates. 45 As previously noted, patients who know they have HIV are less likely to infect others at a time when the disease is highly infectious. For every one less HIV infection, $385,000 in estimated lifetime care and treatment costs could be averted, said Schmid. These factors indicate that 4 th generation testing, which can detect some of the missed patients, may have economic benefits. This message was supported by a health economics modeling study published in HIV Clinical Trials that compared 3 rd and 4 th generation HIV testing. The study concluded that 4 th generation testing may be a cost-effective method for the detection of HIV infection. Factors that contribute to cost effectiveness include more cases being correctly identified and patients receiving earlier treatment. Combined with patient behavior modifications, this may lead to fewer transmissions, longer life expectancy and higher quality of life. 46 Identified Infections About 90% of acute/recent HIV infections would be identified with HIV Combo test. Reference: Pandori et al, J Clin Microbiol, 2009 August; 47(8): 2639-2642 The modeling study estimated that 4 th generation testing could have avoided 26 cases of HIV per 1.5 million screenings, and that s if the patient infects only one partner, said Dr. Leone. When you consider that the lifetime cost of HIV treatment is nearly $400,000 per case, that s millions of dollars of potential costs to the healthcare system, not including the cost of downstream transmission to additional partners. Another consideration, particularly for hospital CEOs and CMOs, is the possibility that 3 rd generation HIV testing at some point may no longer be considered adequate as a standard of care, as is the case in other countries. It s not unreasonable, then, to consider whether the use of a test that falls below the preferred standard of care could, potentially, create exposure to liability.

Conclusion Identifying acute infections has long been one of our nation s biggest HIV prevention challenges, since these infections eluded traditional testing technologies. But with consistent and widespread use of this new testing method, we can diagnose people several weeks earlier than before. CDC is supporting laboratories to adopt this new approach as quickly as possible. Dr. Jonathan Mermin, Director, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention Despite advances in HIV testing and unanimous agreement on the importance of early detection, each year for more than a decade about 50,000 people have been diagnosed with HIV, 47 many of them late in their illness. Historically 24%-43% of patients who enter treatment are found to do so late in the infection; 48 in 2010, 32% received an AIDS diagnosis within one year of testing HIV positive. 49 The CDC estimates that just one in four people living with HIV in the country are successfully navigating a continuum of care that results in a suppressed viral load, which is necessary for their own health and critical to stopping further transmission of HIV. 50 In addition, patients who begin treatment for HIV infection well after the infection is established have much higher overall treatment costs than patients who begin treatment early in the disease process. 51 Routine screening of adult patients in all health care settings would be a major step forward in the fight against HIV. Equally important, however, is making sure that patients receive the right kind of test capable of diagnosing acute HIV, which is highly infectious and may not be detected by traditional antibody-only tests. New 4 th generation tests can detect HIV earlier than traditional antibody-only tests. Abbott s ARCHITECT HIV Ag/Ab HIV Combo assay can detect HIV up to 20 days earlier. 52 These tests are the initial screening tests in a new testing algorithm recommended in CDC and CLSI guidelines, which is being adopted by hospitals and public health agencies nationwide. Everyone from hospital executives and lab directors to public health officials and providers can help slow the spread of HIV by spreading the word about the importance of early detection and making sure patients receive the right tests at the right time. With greater vigilance and the use of 4 th generation testing, we can come ever closer to realizing a common goal that no patient seeking care is ever sent home with an undiagnosed HIV infection. We can t afford to miss HIV. Economic Benefits of Early HIV Diagnosis Hospitalization rate Incident morbidity Acute care lifetime cost reduction Decrease transmission with HAART therapy $ 385,200 ESTIMATED LIFETIME COST OF HIV CARE* * For adults who initiate ART with CD4 cell counts <350/µL

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