Clinical Infectious Diseases Advance Access published May 27, 2014 1
HIV and HCV infection in the United States: Whom and How to Test
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Nivedha Panneer1, Erik Lontok1, Bernard M. Branson2, Chong-Gee Teo3, Corinna Dan4, Monica Parker5, Joanne D. Stekler6, Alfred DeMaria, Jr.7, Veronica Miller1 1
Forum for Collaborative HIV Research, University of California, Berkeley, Washington, DC
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Division of HIV/AIDS Prevention, National Center for HIV, STD and TB Prevention, U.S.
Viral Hepatitis Laboratory Diagnostics, National Center for HIV, STD and TB Prevention, U.S.
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Centers for Disease Control and Prevention, Atlanta, GA
Office of HIV/AIDS Policy, U.S. Department of Health and Human Services, Washington, DC
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Wadsworth Center, New York State Department of Health, Albany, NY
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Department of Medicine, University of Washington & Public Health - Seattle & King County
HIV/STD Program, Seattle, WA
Bureau of Infectious Disease, Massachusetts Department of Public Health, Jamaica Plain, MA
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CORRESPONDENCE: Nivedha Panneer, Forum for Collaborative HIV Research, University of California, Berkeley, 1608 Rhode Island Avenue NW, Suite 212; Washington DC 20036; E-
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mail:
[email protected]; Tel.: +1 202 974 6220; Fax: +1 202 872 4316.
BRIEF 40-WORD SUMMARY:
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We review current recommendations on whom to test and how to test for HIV and HCV in the United States and identify some remaining challenges.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e‐mail:
[email protected].
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Centers for Disease Control and Prevention, Atlanta, GA
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Abstract In the United States, of the 1.1 million persons infected with human immunodeficiency virus
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(HIV) and the 2.7 million infected with hepatitis C virus (HCV), approximately 16% and 50%, respectively, are unaware of their infection. Highly effective treatments have turned both
diseases into manageable conditions, and in the case of hepatitis C, a disease that can be cured.
Early diagnosis is imperative so infected persons can take measures to stay healthy, get into care,
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recommendations provided by the Centers for Disease Control and Prevention (CDC) and the
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United States Preventive Services Task Force on whom to screen for HIV and HCV infections, and recommendations from the CDC, the Association of Public Health Laboratories, and the
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Clinical and Laboratory Standards Institute on how to test for these infections.
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benefit from therapy, and reduce the risk of transmission. In this report, we review current
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Introduction In the United States, approximately 1.1 million persons are infected with human
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immunodeficiency virus (HIV) [1], and an estimated 50,000 new infections occur each year [2]. Disease burden is highest in men who have sex with men (MSM), in particular, young, black
MSM. In comparison, the prevalence of chronic hepatitis C virus (HCV) infection is nearly three
times that of HIV with an estimated 2.7 million persons infected with HCV [3], and an estimated
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and disease, attributed to injecting-drug use and/or health care exposures, such as unscreened
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blood transfusions during the 1970s-1980s [4].
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HIV primarily infects CD4+ T lymphocytes and causes deterioration of the immune system within weeks to months followed by deterioration of overall immune function over months to
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years [5]. HCV infects hepatocytes with slow, and often silent, disease progression over several decades [6]. Both HIV and HCV are blood-borne viruses and are transmitted via contaminated blood (such as from shared injection equipment, needle stick injury) or contaminated blood products. In the United States, sexual transmission among MSM is the primary route for HIV
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transmission [1]. Although sexual transmission of HCV occurs among HIV-positive MSM [7],
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injecting-drug use is the primary risk factor for HCV transmission [8].
Highly potent and effective treatment for HIV has turned HIV disease, once considered a deathsentence, into a manageable condition. With early treatment, life expectancies are comparable to those of the general population [9, 10]. The unparalleled advances in HCV treatment within the
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17,000 new infections in 2010. Persons born during 1945-1965 bear the brunt of HCV infection
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past few years, from interferon-containing regimens with 40% sustained virologic response (SVR) rates in genotype-1 treatment-naive individuals [11] to all-oral, direct acting antiviral
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(DAA) regimens with nearly 100% SVR regardless of the genotype of the infecting HCV [12],
have transformed an illness once thought to be incurable to one for which eradication is possible.
for HIV [1] and 50% for HCV [13]), effective treatment provides the impetus for increased
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screening. Accurate testing and early diagnosis allow infected persons to take measures to stay healthy, get into care, benefit from therapy and reduce the risk of transmission. This report provides an overview of current recommendations on whom to test and how to test for HIV and
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HCV in the United States and identifies some remaining challenges.
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Whom to test
Health-care providers rely on the Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force (USPSTF) for guidance regarding screening for
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HIV and HCV. The CDC makes evidence-based recommendations relating to the impact of current HIV and HCV screening practices on diagnosis as well as public health outcomes in the US, including patient populations that may not have been reached with prior testing
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recommendations. The USPSTF, an independent body of experts in preventive medicine and primary care, reviews evidence for preventive services, including screening, and makes recommendations (graded on a hierarchy of A, B, C or D or I, for insufficient) based on the strength of evidence and the expected benefit and harm associated with the preventive service.
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With a significant proportion of infected persons unaware of their infection (approximately 16%
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Section 2713 of the Patient Protection and Affordable Care Act (PPACA) requires insurers to cover preventive services with a USPSTF ‘A’ or ‘B’ grade without patient cost-sharing [14].
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Alignment of recommendations from the CDC and USPSTF facilitates wide-spread adoption of HIV and HCV testing recommendations, and improves progress toward national goals outlined
HIV
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In 2006, the CDC recommended that providers perform routine opt-out screening for HIV for persons aged 13-64 years regardless of risk in all health-care settings in which the prevalence of undiagnosed HIV is > 0.1%. This recommendation was supported by a large body of evidence
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demonstrating the benefits of routine screening, including increased diagnosis of HIV infection, greater patient acceptance when testing is offered to everyone without risk-based targeting, and
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reduced HIV transmission to partners from infected persons who are aware of their infection [17]. In 2013, the USPSTF upgraded HIV screening for individuals not at increased risk for HIV from a ‘C’ to an ‘A’ grade, based on the benefits of ART initiation for HIV-positive persons with CD4+ T lymphocyte count below 500 cells/mm3 and its effectiveness for reducing transmission
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to uninfected partners [18, 19]. This close agreement between CDC and USPSTF recommendations promotes a concerted, national effort to increase HIV diagnosis and provide
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opportunities for earlier linkage to care and treatment. The CDC and USPSTF also recommend at least annual retesting for persons at high risk for HIV infection.
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in the National HIV/AIDS Strategy [15] and the Viral Hepatitis Action Plan [16].
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HCV In 2012, the CDC recommended one-time testing of all persons born during 1945-1965 [4],
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expanding on previous guidelines [20] which recommended routine HCV testing in persons who
ever injected illegal drugs, who received blood transfusions or organ transplants before July 1992 or from a donor later known to be HCV-positive, who were exposed to HCV-positive blood
through a healthcare setting, or who were born to HCV-positive women. As persons born during
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mortality, the 2012 recommendation aimed to increase HCV diagnoses in persons in this cohort
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who have largely been missed by risk-factor screening. In 2013, USPSTF revised their recommendations from a ‘C’ in the draft recommendation to a ‘B’ grade to offer one-time
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screening for persons born during 1945-1965. This revision was based on the enlarging evidence base showing associations between achieving SVR and improved clinical outcomes, as well as
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improved SVR from available therapy [21]. USPSTF also amended their long standing recommendation from an ‘I’ to a ‘B’ grade to screen persons at high risk of infection.
CDC and USPSTF recommendations did not offer guidance on how frequently persons at
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increased risk of infection should receive HCV testing. The latest guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of
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America (IDSA) recommend at least annual testing for persons who inject drugs and HIVinfected MSM, recognizing the high incidence of HCV infection in these subgroups [22].
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1945-1965 represent the majority of individuals with rising HCV associated morbidity and
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How to test
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HIV The CDC, Association of Public Health Laboratories (APHL), and the Clinical and Laboratory
Standards Institute (CLSI) constitute the main sources for guidance on laboratory testing for the diagnosis of HIV infection. The CLSI’s Criteria for Laboratory Testing and Diagnosis of
by many laboratorians and provides guidance on types of initial and supplement tests, alternative
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testing algorithms, test result interpretation and result reporting in special situations, as well as how to establish a quality control program for HIV testing [23]. For laboratory HIV testing, the CDC and APHL proposed a testing algorithm, herein referred to as the 2010 HIV testing
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algorithm, that employs, as the initial test, an antigen/antibody (Ag/Ab) immunoassay capable of detecting HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen1 (Figure 1). If the initial test is
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reactive, it is followed by an HIV-1/HIV-2 antibody differentiation immunoassay. Positive results on the antibody differentiation immunoassay establish the diagnosis of HIV-1 or HIV-2 [24]. Specimens reactive on the initial Ag/Ab immunoassay that are negative or indeterminate on the antibody differentiation immunoassay are tested with HIV-1 NAT, which, if positive,
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identifies acute HIV-1 infection. Negative NAT results indicate false-positive results from the initial Ag/Ab immunoassay. The 2010 HIV testing algorithm facilitates detection of early HIV-1 infection, produces fewer indeterminate results, and allows more timely identification of HIV-2
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infection compared to the previous HIV testing algorithm that relied on HIV-1 Western blot for confirming reactive results [25,26]. The sequence of subsequent tests in the 2010 HIV testing 1
Commercially available tests are classified into generations depending on the various serologic and virologic markers detected. First and second generation tests detect IgG antibody using viral lysate and recombinant antigens, respectively. Third generation tests detect IgG and IgM antibodies, whereas fourth-generation tests detect p24 antigen and IgG and IgM antibodies.
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Human Immunodeficiency Virus Infection; Approved Guideline is considered standard of practice
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algorithm will detect additional infections negative by Western blot even if laboratories use a third generation immunoassay as the initial test. A turn-around time of one day is possible for the
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majority of samples in which antibody is present, but results may be delayed for the small
number of samples that need NAT if they require transport to a reference laboratory for testing [24].
number of Food and Drug Administration (FDA)-approved supplemental tests. Currently, the
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Multispot HIV-1/HIV-2 Rapid Test is the only FDA-approved HIV-1/HIV-2 differentiation immunoassay that can be used after a reactive Ag/Ab immunoassay result. Moreover, the
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APTIMA HIV-1 RNA Qualitative Assay is the only NAT FDA-approved for the diagnosis of HIV-1 infection. Quantitative NAT (viral load) assays are more widely available than qualitative
diagnosis.
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NAT and could reduce turnaround time for test results but they are not FDA-approved for HIV
Point-of-care rapid HIV tests are useful for outreach settings to facilitate testing among hard-toreach populations, for persons who might not return for laboratory test results, and in some
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circumstances where immediate test results are required for clinical decision making. Sensitivity of rapid HIV tests for established infection is comparable to that of laboratory assays. However,
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they become reactive for antibodies later than laboratory-based third and fourth generation immunoassays.
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One challenge for widespread implementation of the 2010 HIV testing algorithm is the limited
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After reactive results from any HIV rapid test, including the Alere Determine HIV-1/2 Ag/Ab Combo rapid test, specimens should be tested according to the full 2010 HIV testing algorithm,
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starting with the laboratory-based Ag/Ab immunoassay. Table 1 provides a list of FDA-approved tests for HIV diagnosis that can be used as part of the 2010 HIV testing algorithm.
Owing to the changes in diagnostic criteria provided by the 2010 HIV testing algorithm, the
definition for HIV infection to include infection that occurred within 180 days (including acute
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HIV infection) classified as Stage 0 and specific criteria for defining a case as HIV-2 [27].
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HCV
As there is no CLSI guideline for HCV testing, the testing sequence recommended by the CDC,
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hereby referred as the 2013 HCV testing algorithm, provides guidance on how to test for HCV infection in clinical practice. Highlights of the algorithm include NAT for antibody-reactive specimens to identify current HCV infection, removal of the Chiron RIBA HCV Strip Immunoblot Assay (RIBA) for supplemental testing, and accommodation of the OraQuick HCV Rapid Antibody test [28] (Figure 2). The algorithm starts with an immunoassay (conducted in the
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laboratory or using the OraQuick HCV Rapid Antibody Test), which if reactive, is followed by NAT. A nonreactive immunoassay result requires no further testing, except for persons who are
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immunocompromised or have had recent exposure to HCV and are at risk of having acute infection. A positive NAT result indicates current HCV infection, requiring linkage to care. A negative NAT result, indicating absence of current infection, requires no further testing in most instances. Repeat NAT is recommended in the following circumstances: recent HCV exposure
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CDC and the Council for State and Territorial Epidemiologists revised the surveillance case
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within the past six months, clinical evidence of disease or mishandling or improper storage of the specimen. Table 2 provides a list of FDA-approved tests for HCV diagnosis that can be used
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according to the 2013 HCV testing algorithm.
It is critical to identify currently infected individuals (most of whom are chronically infected)
early so steps can be taken to limit disease progression and reduce risks for HCV transmission.
as sensitive as laboratory-based immunoassays for detecting early infection and thus not
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incorporated in the algorithm, the OraQuick HCV Rapid Antibody test is comparable in performance to laboratory-based HCV immunoassays and thus can be used for primary HCV
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screening. Reflex NAT testing on all antibody-reactive tests may be conducted to facilitate faster test result reporting back to the provider and patient thus allowing for earlier linkage to care and treatment. Although the logistical complexities of specimen storage and retrieval may present
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challenges to performing reflex NAT, stability studies have indicated that plasma samples can be stored at 4oC, 25oC or 37oC for up to seven days without significantly affecting HCV RNA detection [29].
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One challenge for the implementation of the 2013 HCV algorithm is the ambiguity that can arise following a reactive antibody test and a negative NAT result, which signifies resolved infection
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or biological false positivity [28]. An immunoblot-based assay capable of distinguishing between true and false antibody reactivity, when available, might provide further clarity.
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In contrast to the 2010 HIV testing algorithm for which HIV rapid tests are not considered to be
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The HCV core antigen assay presents an alternative to NAT due to its comparable sensitivity to detect acute infection [30] as well as its predicted lower costs to run test specimens, since it uses
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immunoassay reagents and techniques that are less expensive and require less technical expertise and training compared to NAT. Widely accepted in Europe, HCV core antigen testing has potential in the United States to replace HCV NAT.
NATs, currently the only FDA-approved tests capable of detecting viremia, detect (qualitatively)
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or measure (quantitatively) viral RNA in peripheral blood. Historically, qualitative NATs, sensitive for detecting viral RNA, were initially FDA-approved for screening blood donations,
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and later for diagnosis. Quantitative NATs (viral load assays) were FDA-approved for disease prognosis and monitoring treatment management. With advances in molecular amplification
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technologies and the advent of real-time PCR, quantitative NAT now have a very broad linear range and comparable sensitivity to qualitative NAT [31, 32]. Nevertheless, clinical laboratories are still restricted by stipulations in device package inserts and cannot reflexively test antibodyreactive specimens with a quantitative NAT to confirm infection. Because such use is off-label, the Center for Medicare and Medicaid Services (CMS) which regulates laboratory testing
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through the Clinical Laboratory Improvement Amendments, requires laboratories to conduct separate validation studies to use quantitative NAT for diagnosis [33]. These validation studies
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are beyond the capacity of many laboratories to conduct. Moreover, lack of standardized criteria for how to conduct validation studies can result in variation in bench and analytic methodologies across laboratories [34].
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Quantitative NAT for HIV and HCV
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Although the FDA regulates device marketing and the CMS regulates laboratory testing, neither body regulates the practice of medicine. Recognizing that quantitative NAT now has a low limit
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of detection, professional clinical societies advocate using quantitative NAT for confirming the presence of HCV [22] and HIV [35]. This approach permits streamlined and cost-effective
diagnosis of current infection with simultaneous determination of viral load prior to initiation of
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Conclusions
Highly efficacious treatments for HIV and HCV and the long-term benefits associated with such treatment drive the demand for testing. HIV treatment has transformed a life-threatening illness
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to a chronic condition. Although still requiring life-long treatment, early treatment can improve survival such that life expectancy for a person with HIV infection can be as long as that of
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uninfected persons [9,10]. Further, the HPTN 052 study demonstrated that initiation of therapy in infected individuals reduces the risk of HIV transmission by 96%, so treatment is a form of prevention [19].The U.S. Department of Health and Human Services panel on antiretroviral guidelines for HIV-infected adults and adolescents recommends antiretroviral therapy for all
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HIV-infected individuals [36] as an important tool to improve health outcomes, increase survival
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and prevent new infections.
For HCV, what constitutes standard of care is changing rapidly with shorter and more tolerable treatment regimens being continuously introduced. Thus, boceprevir and telaprevir, the firstgeneration protease inhibitors approved by FDA in 2011, are no longer recommended by
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therapy.
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AASLD and IDSA for treating the majority of HCV-infected persons [22]. Recently approved simeprevir and sofosbuvir represent the current standard of care [22] when used with pegylated
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interferon and/or ribavirin, or with each other in an all-oral regimen, achieving SVR rates
reaching 100% [37]. SVR is predictive of lower all-cause mortality, reduced rates of liver-related death and overall better quality of life outcomes [38]. Current and anticipated all-oral therapy regimens that exclude ribavirin open new possibilities for expanding the number of HCV-
morbidity and mortality, and eliminating HCV. Although the high cost of treatment [39] remains
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the main barrier to access, the rich pipeline of DAAs in phase 2 and 3 clinical trials that are expected to enter the market in 2014-2015 promise more competition that can reduce treatment
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costs. Modeling studies of HCV treatment scale-up in persons who inject drugs support the potential of HCV treatment as a preventative measure that can dramatically reduce prevalence
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[40].
The National HIV/AIDS Strategy [15] and the Viral Hepatitis Action Plan [16] provide an overall framework to address the burden of HIV and HCV in the United States by specifying a
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series of goals: increase access to care, improve health outcomes for infected individuals and decrease new infections. The CDC and USPSTF recommendations on whom to screen along with the CDC 2010 HIV and 2013 HCV testing algorithms are key to achieving these goals. No
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matter how efficacious current and coming therapies may be, testing is the critical first step for infected individuals to engage in the health-care system to receive care and treatment.
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infected persons receiving therapy, avoiding significant adverse treatment events, reducing HCV
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Notes
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The Forum for Collaborative HIV Research Funders (2013-2014) has received funding from AbbVie, Abbott Molecular, Achillion, Boehringer Ingelheim, Bristol Myers Squibb, Celera, DDL Diagnostic, Genentech, Gilead Sciences, GSK, Idenix, Illumina, Inc., Janssen, Kaiser
Permanente, Medscape, Merck Laboratories, Monogram, Novartis, Pacific Bioscences Inc, PPD,
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The authors have no other disclosures.
DISCLAIMER: The views expressed in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention or the
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Department of Health and Human Services. Use of trade names is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services, the Public
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Health Service, or the Centers for Disease Control and Prevention.
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Inc., Quintiles, Roche Molecular diagnostics, Tobira, Vertex, and ViiV Healthcare.
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antivirals. Hepatology 2013; 58(5): 1598-609.
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Figure Legends Figure 1. The 2010 HIV testing algorithm employs an HIV-1/HIV-2 Ag/Ab immunoassay
followed, if reactive, by a supplemental HIV-1/HIV-2 differentiation immunoassay or NAT for identifying established and acute infections, respectively.
Evaluations of a New HIV Diagnostic Testing Algorithm — United States, 2011–2013. MMWR 2013;
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62:489-94.
Figure 2. The 2013 HCV testing algorithm employs an HCV immunoassay followed, if reactive, by NAT to identify current infection.
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Source: Centers for Disease Control and Prevention. Testing for HCV infection: an update of guidance
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Source: Centers for Disease Control and Prevention. Detection of Acute HIV Infection in Two
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Table 1. FDA-Approved Tests for the Diagnosis of HIV Infection
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Avioq HIV-1 Microelisa System
Avioq
IgG Ab
Bio-Rad GS HIV-1/2 PLUS O
Bio-Rad Laboratories
IgG and IgM Ab
Bio-Rad GS HIV Combo Ag/Ab EIA
Bio-Rad Laboratories
Assay
Conventional enzyme immunoassays
Advia Centaur HIV 1/O/2 Enhanced Assay
Siemens
Ortho Vitros Anti-HIV 1+2
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HIV-1 gp41, gp160, group O, p24 monoclonal antibodies; HIV-2 gp36
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Abbott Laboratories
IgG and IgM Ab p24 Ag
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Abbott Architect HIV Ag/Ab Combo
HIV-1 p24, gp160, group O; HIV-2 gp36
HIV-1 gp41, group O, p24 monoclonal antibodies; HIV-2 gp36 HIV-1 gp41/120, p24, group O; HIV2 gp36
Ortho-Clinical Diagnostics
IgG and IgM Ab
HIV-1 gp41, gp41/120, p24; HIV-2 gp36
Alere Clearview Complete HIV 1/2
Chembio Diagnostics
IgG Ab
HIV-1 gp41, gp120; HIV-2 gp36
Alere Clearview HIV 1/2 Stat Pak
Chembio Diagnostics
IgG Ab
HIV-1 gp41, gp120; HIV-2 gp36
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IgG and IgM Ab
Alere
IgG Ab and p24 Ag
HIV-1 gp41, gp120, p24 monoclonal antibodies; HIV-2 gp36.
Chembio DPP HIV 1/2 Assay
Chembio Diagnostics
IgG Ab
HIV-1 gp 41, gp120; HIV-2 gp36
INSTI HIV-1 Antibody Test Kit
Biolytical Laboratories
IgG Ab
HIV-1 gp41; HIV-2 gp36
Multispot HIV-1/HIV-2 Rapid Test
Bio-Rad Laboratories
IgG Ab
HIV-1 gp41; HIV-2 gp36
OraQuick Advance Rapid
Orasure
IgG Ab
HIV-1 gp41; HIV-2 gp36
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Alere Determine HIV 1/2 Ag/Ab Combo
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Chemiluminescent Assays
Viral lysate, gp160
IgG and IgM Ab p24 Ag
Markers used for detection*
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Manufacturer
Analytes detected* (IgG Ab, IgM Ab, p24 Ag, HIV-1 RNA)
24 HIV-1/2 Antibody Test
Technologies
Reveal G3 Rapid HIV-1 Antibody Test
MedMira
IgG Ab
Uni-Gold Recombigen HIV-1/2
Trinity BioTech
IgG and IgM Ab
Qualitative NAT APTIMA HIV-1 RNA Qualitative Assay
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HIV-1 gp41, gp120 HIV-1 gp41, gp120; HIV-2 gp36
Amplification method; target
Gen-Probe
HIV-1 RNA
TMA; HIV-1 LTR and polymerase genes
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Abbreviations: HIV, human immunodeficiency virus; HCV, hepatitis C virus; Ab, antibody *Source: Device package inserts and FDA Summaries of Safety and Effectiveness
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Table 2: FDA-Approved Tests for the Diagnosis of HCV Infection Analytes detected* (IgG Ab, IgM Ab, HCV RNA)
Markers used for detection*
Abbott Laboratories
IgG Ab
HCr43, c200, c100-3
Abbott Architect AntiHCV
Abbott Laboratories
IgG and IgM Ab
Advia Centaur Anti-HCV Assay
Siemens
Elecsys Anti-HCV
Roche Diagnostics
Ortho Vitros Anti-HCV
Ortho-Clinical Diagnostics
IgG Ab
c200, c22-3, NS5
Orasure Technologies
IgG Ab
Core, NS3, NS4
Abbott AxSYM AntiHCV
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HCr-43, c100-3
IgG Ab
c200, c22, NS5
IgG and IgM Ab
Core, NS3, NS4
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Rapid Test OraQuick HCV Rapid Antibody Test
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Chemiluminescent Assays
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Conventional enzyme immunoassays
Amplification method; target
Qualitative NAT
Roche Molecular
HCV RNA
Semi-automated RTPCR; 5’UTR
Versant HCV RNA Qualitative Assay
Gen-Probe
HCV RNA
Semi-automated TMA; 5’UTR
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COBAS Amplicor HCV v2.0
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Abbreviations: HIV, human immunodeficiency virus; HCV, hepatitis C virus; Ab, antibody *Source: Device package inserts and FDA Summaries of Safety and Effectiveness
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Manufacturer
Assay
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