HIV Diagnostics: Current Recommendations and Opportunities for Improvement.

Profound changes in technology have revolutionized laboratory testing for human immunodeficiency virus (HIV) since the first laboratory enzyme immunoassays that detected only immunoglobulin G (IgG) antibodies. Instrumented fourth-generation random-access chemiluminescent assays are now recommended for initial screening because they become reactive in as little as 2 weeks after infection. Using HIV-1 RNA viral load assays after a reactive initial test could confirm infection and provide useful clinical information. Early initiation of antiretroviral therapy and use of preexposure prophylaxis can alter the evolution of biomarkers and assay reactivity, leading to ambiguous test results.

Direct Diagnostic Tests for Lyme Disease.

Borrelia burgdorferi was discovered to be the cause of Lyme disease in 1983, leading to seroassays. The 1994 serodiagnostic testing guidelines predated a full understanding of key B. burgdorferi antigens and have a number of shortcomings. These serologic tests cannot distinguish active infection, past infection, or reinfection. Reliable direct-detection methods for active B. burgdorferi infection have been lacking in the past but are needed and appear achievable. New approaches have effectively been applied to other emerging infections and show promise in direct detection of B. burgdorferi infections.

It's all in the timing: Acceptability of a financial incentive intervention for linkage to HIV care in the HPTN 065 (TLC-Plus) study.

The HPTN 065 (TLC-Plus) study tested the feasibility and effectiveness of using financial incentives (FIs) to increase linkage to care (L2C) among individuals with newly diagnosed HIV and those out of care in the Bronx, NY and Washington, DC. Qualitative data collection with a subset of participating patients and staff focused on experiences with and attitudes about the FI intervention. Semi-structured interviews were conducted with 15 patients and 14 site investigators. Four focus group discussions were conducted with a total of 15 staff members. The use of FIs for L2C was generally viewed favorably. Patients were grateful and benefited financially, but sites had some challenges implementing the program. Challenges included the timing and sensitive introduction of the intervention immediately after an HIV diagnosis, negative attitudes towards paying people for health behaviors, and the existence and strength of existing linkage programs. Future programs should consider optimal timing and presentation of FIs.

Acute HIV Discovered During Routine HIV Screening With HIV Antigen-Antibody Combination Tests in 9 US Emergency Departments.

STUDY OBJECTIVE: Newer combination HIV antigen-antibody tests allow detection of HIV sooner after infection than previous antibody-only immunoassays because, in addition to HIV-1 and -2 antibodies, they detect the HIV-1 p24 antigen, which appears before antibodies develop. We determine the yield of screening with HIV antigen-antibody tests and clinical presentations for new diagnoses of acute and established HIV infection across US emergency departments (EDs). METHODS: This was a retrospective study of 9 EDs in 6 cities with HIV screening programs that integrated laboratory-based antigen-antibody tests between November 1, 2012, and December 31, 2015. Unique patients with newly diagnosed HIV infection were identified and classified as having either acute HIV infection or established HIV infection. Acute HIV infection was defined as a repeatedly reactive antigen-antibody test result, a negative HIV-1/HIV-2 antibody differentiation assay, or Western blot result, but detectable HIV ribonucleic acid (RNA); established HIV infection was defined as a repeatedly reactive antigen-antibody test result and a positive HIV-1/HIV-2 antibody differentiation assay or Western blot result. The primary outcomes were the number of new HIV diagnoses and proportion of patients with laboratory-defined acute HIV infection. Secondary outcomes compared reason for visit and the clinical presentation of acute HIV infection. RESULTS: In total, 214,524 patients were screened for HIV and 839 (0.4%) received a new diagnosis, of which 122 (14.5%) were acute HIV infection and 717 (85.5%) were established HIV infection. Compared with patients with established HIV infection, those with acute HIV infection were younger, had higher RNA and CD4 counts, and were more likely to have viral syndrome (41.8% versus 6.5%) or fever (14.3% versus 3.4%) as their reason for visit. Most patients with acute HIV infection displayed symptoms attributable to acute infection (median symptom count 5 [interquartile range 3 to 6]), with fever often accompanied by greater than or equal to 3 other symptoms (60.7%). CONCLUSION: ED screening using antigen-antibody tests identifies previously undiagnosed HIV infection at proportions that exceed the Centers for Disease Control and Prevention's screening threshold, with the added yield of identifying acute HIV infection in approximately 15% of patients with a new diagnosis. Patients with acute HIV infection often seek ED care for symptoms related to seroconversion.

Advances in Serodiagnostic Testing for Lyme Disease Are at Hand.

The cause of Lyme disease, Borrelia burgdorferi, was discovered in 1983. A 2-tiered testing protocol was established for serodiagnosis in 1994, involving an enzyme immunoassay (EIA) or indirect fluorescence antibody, followed (if reactive) by immunoglobulin M and immunoglobulin G Western immunoblots. These assays were prepared from whole-cell cultured B. burgdorferi, lacking key in vivo expressed antigens and expressing antigens that can bind non-Borrelia antibodies. Additional drawbacks, particular to the Western immunoblot component, include low sensitivity in early infection, technical complexity, and subjective interpretation when scored by visual examination. Nevertheless, 2-tiered testing with immunoblotting remains the benchmark for evaluation of new methods or approaches. Next-generation serologic assays, prepared with recombinant proteins or synthetic peptides, and alternative testing protocols, can now overcome or circumvent many of these past drawbacks. This article describes next-generation serodiagnostic testing for Lyme disease, focusing on methods that are currently available or near-at-hand.

Expanding Hospital Human Immunodeficiency Virus Testing in the Bronx, New York and Washington, District of Columbia: Results From the HPTN 065 Study.

Background: Human immunodeficiency virus (HIV) testing is critical for both HIV treatment and prevention. Expanding testing in hospital settings can identify undiagnosed HIV infections. Methods: To evaluate the feasibility of universally offering HIV testing during emergency department (ED) visits and inpatient admissions, 9 hospitals in the Bronx, New York and 7 in Washington, District of Columbia (DC) undertook efforts to offer HIV testing routinely. Outcomes included the percentage of encounters with an HIV test, the change from year 1 to year 3, and the percentages of tests that were HIV-positive and new diagnoses. Results: From 1 February 2011 to 31 January 2014, HIV tests were conducted during 6.5% of 1621016 ED visits and 13.0% of 361745 inpatient admissions in Bronx hospitals and 13.8% of 729172 ED visits and 22.0% of 150655 inpatient admissions in DC. From year 1 to year 3, testing was stable in the Bronx (ED visits: 6.6% to 6.9%; inpatient admissions: 13.0% to 13.6%), but increased in DC (ED visits: 11.9% to 15.8%; inpatient admissions: 19.0% to 23.9%). In the Bronx, 0.4% (408) of ED HIV tests were positive and 0.3% (277) were new diagnoses; 1.8% (828) of inpatient tests were positive and 0.5% (244) were new diagnoses. In DC, 0.6% (618) of ED tests were positive and 0.4% (404) were new diagnoses; 4.9% (1349) of inpatient tests were positive and 0.7% (189) were new diagnoses. Conclusions: Hospitals consistently identified previously undiagnosed HIV infections, but universal offer of HIV testing proved elusive.

"It Makes You Feel Like Someone Cares" acceptability of a financial incentive intervention for HIV viral suppression in the HPTN 065 (TLC-Plus) study.

BACKGROUND: HPTN 065 (TLC-Plus) evaluated the feasibility and effectiveness of providing quarterly $70 gift card financial incentives to HIV-infected patients on antiretroviral therapy (ART) to encourage ART adherence and viral suppression, and represents the largest study to-date of a financial incentive intervention for HIV viral suppression. A post-trial qualitative substudy was undertaken to examine acceptability of the financial incentives among those receiving and implementing the intervention. METHODS: Between July and October 2013, semi-structured interviews were conducted with 72 patients and 12 investigators from 14 sites; three focus groups were conducted with 12 staff from 10 sites. Qualitative data collection elicited experiences with and attitudes about the intervention, including philosophical viewpoints and implementation experiences. Transcripts were analyzed in NVivo 10. Memos and matrices were developed to explore themes from different participant group perspectives. RESULTS: Patients, investigators, and staff found the intervention highly acceptable, primarily due to the emotional benefits gained through giving or receiving the incentive. Feeling rewarded or cared for was a main value perceived by patients; this was closely tied to the financial benefit for some. Other factors influencing acceptability for all included perceived effectiveness and health-related benefits, philosophical concerns about the use of incentives for health behavior change, and implementation issues. The termination of the incentive at the end of the study was disappointing to participants and unexpected by some, but generally accepted. CONCLUSION: Positive experiences with the financial incentive intervention and strategies used to facilitate implementation led to high acceptability of the intervention, despite some reluctance in principle to the use of incentives. The findings of this analysis provide encouraging evidence in support of the acceptability of a large-scale financial incentive intervention for HIV viral suppression in a clinical setting, and offer valuable lessons for future applications of similar interventions.

Costs of Expanded Rapid HIV Testing in Four Emergency Departments.

OBJECTIVE: The HIV Prevention Trials Network (HPTN) 065 trial sought to expand HIV screening of emergency department (ED) patients in Bronx, New York, and Washington, D.C. This study assessed the testing costs associated with different expansion processes and compared them with costs of a hypothetical optimized process. METHODS: Micro-costing studies were conducted in two participating EDs in each city that switched from point-of-care (POC) to rapid-result laboratory testing. In three EDs, laboratory HIV testing was only conducted for patients having blood drawn for clinical reasons; in the other ED, all HIV testing was conducted with laboratory testing. Costs were estimated through direct observation and interviews to document process flows, time estimates, and labor and materials costs. A hypothetical optimized process flow used minimum time estimates for each process step. National wage and fringe rates and local reagent costs were used to determine the average cost (excluding overhead) per completed nonreactive and reactive test in 2013 U.S. dollars. RESULTS: Laboratory HIV testing costs in the EDs ranged from $17.00 to $23.83 per completed nonreactive test, and POC testing costs ranged from $17.64 to $37.60; cost per completed reactive test ranged from $89.29 to $123.17. Costs of hypothetical optimized HIV testing with automated process steps were approximately 45% lower for nonreactive tests and 20% lower for reactive tests. The cost per ED visit to conduct expanded HIV testing in each hospital ranged from $1.21 to $3.96. CONCLUSION: An optimized process could achieve additional cost savings but would require an investment in electronic system interfaces to further automate testing processes.

HIV Testing among Outpatients with Medicaid and Commercial Insurance.

OBJECTIVE: To assess HIV testing and factors associated with receipt of testing among persons with Medicaid and commercial insurance during 2012. METHODS: Outpatient and laboratory claims were analyzed from two databases: all Medicaid claims from six states and all claims from Medicaid health plans from four other states and a large national convenience sample of patients with commercial insurance in the United States. We excluded those aged <13 years and >64 years, enrolled <9 of the 12 months, pregnant females, and previously diagnosed with HIV. We identified patients with new HIV diagnoses that followed (did not precede) the HIV test, using HIV ICD-9 codes. HIV testing percentages were assessed by patient demographics and other tests or diagnoses that occurred during the same visit. RESULTS: During 2012, 89,242 of 2,069,536 patients (4.3%) with Medicaid had at least one HIV test, and 850 (1.0%) of those tested received a new HIV diagnosis. Among 27,206,804 patients with commercial insurance, 757,646 (2.8%) had at least one HIV test, and 5,884 (0.8%) of those tested received a new HIV diagnosis. During visits that included an HIV test, 80.2% of Medicaid and 83.0% of commercial insurance claims also included a test or diagnosis for a sexually transmitted infection (STI), and/or Hepatitis B or C virus at the same visit. CONCLUSIONS: HIV testing primarily took place concurrently with screening or diagnoses for STIs or Hepatitis B or C. We found little evidence to suggest routine screening for HIV infection was widespread.

Monitoring HIV Testing in the United States: Consequences of Methodology Changes to National Surveys.

OBJECTIVE: In 2011, the National Health Interview Survey (NHIS), an in-person household interview, revised the human immunodeficiency virus (HIV) section of the survey and the Behavioral Risk Factor Surveillance System (BRFSS), a telephone-based survey, added cellphone numbers to its sampling frame. We sought to determine how these changes might affect assessment of HIV testing trends. METHODS: We used linear regression with pairwise contrasts with 2003-2013 data from NHIS and BRFSS to compare percentages of persons aged 18-64 years who reported HIV testing in landline versus cellphone-only households before and after 2011, when NHIS revised its in-person questionnaire and BRFSS added cellphone numbers to its telephone-based sample. RESULTS: In NHIS, the percentage of persons in cellphone-only households increased 13-fold from 2003 to 2013. The percentage ever tested for HIV was 6%-10% higher among persons in cellphone-only than landline households. The percentage ever tested for HIV increased significantly from 40.2% in 2003 to 45.0% in 2010, but was significantly lower in 2011 (40.6%) and 2012 (39.7%). In BRFSS, the percentage ever tested decreased significantly from 45.9% in 2003 to 40.2% in 2010, but increased to 42.9% in 2011 and 43.5% in 2013. CONCLUSIONS: HIV testing estimates were lower after NHIS questionnaire changes but higher after BRFSS methodology changes. Data before and after 2011 are not comparable, complicating assessment of trends.

HIV testing updates and challenges: when regulatory caution and public health imperatives collide.

Numerous improvements in HIV testing technology led recently to the first revision of recommendations for diagnostic laboratory testing in the USA in 25 years. Developments in HIV testing continue to produce tests that identify HIV infection earlier with faster turnaround times for test results. These play an important role in identifying HIV infection during the highly infectious acute phase, which has implication for both patient management and public health interventions to control the spread of HIV. Access to these developments, however, is often delayed by the regulatory apparatus for approval and oversight of HIV testing in the USA. This article summarizes recent developments in HIV diagnostic testing technology, outlines their implications for clinical management and public health, describes current systems of regulatory oversight for HIV testing in the USA, and proposes alternatives that could expedite access to improved tests as they become available.

Acceptability of home self-tests for HIV in New York City, 2006.

Data from a 2006 telephone survey representative of New York City adults showed that more than half (56.2%) of those aged 18 to 64 years responded favorably to a question about acceptability of a rapid home HIV test. More than two thirds of certain subpopulations at high risk for HIV reported that they would use a rapid home HIV test, but approximately half who expressed interest had indications of financial hardship. The match of acceptability and HIV risk bodes well for self-testing utility, but cost might impede uptake.

Routine HIV screening in two health-care settings--New York City and New Orleans, 2011-2013.

Approximately 16% of the estimated 1.1 million persons living with human immunodeficiency virus (HIV) in the United States are unaware of their infection and thus unable to benefit from effective treatment that improves health and reduces transmission risk. Since 2006, CDC has recommended that health-care providers screen for HIV all patients aged 13-64 years unless prevalence of undiagnosed HIV infection in their patients has been documented to be <0.1%. This report describes novel HIV screening programs at the Urban Health Plan (UHP), Inc. in New York City and the Interim Louisiana Hospital (ILH) in New Orleans. Data were provided by the two programs. UHP screened a monthly average of 986 patients for HIV during January 2011-September 2013. Of the 32,534 patients screened, 148 (0.45%) tested HIV-positive, of whom 147 (99%) received their test result and 43 (29%) were newly diagnosed. None of the 148 patients with HIV infection were previously receiving medical care, and 120 (81%) were linked to HIV medical care. The ILH emergency department (ED) and the urgent-care center (UCC) screened a monthly average of 1,323 patients from mid-March to December 2013. Of the 12,568 patients screened, 102 (0.81%) tested HIV-positive, of whom 100 (98%) received their test result, 77 (75%) were newly diagnosed, and five (5%) had acute HIV infection. Linkage to HIV medical care was successful for 67 (74%) of 91 patients not already in care. Routine HIV screening identified patients with new and previously diagnosed HIV infection and facilitated their linkage to medical care. The two HIV screening programs highlighted in this report can serve as models that could be adapted by other health-care settings.

HIV and hepatitis C virus infection in the United States: whom and how to test.

In the United States, of the 1.1 million persons infected with human immunodeficiency virus (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 that infected persons can take measures to stay healthy, get into care, benefit from therapy, and reduce the risk of transmission. In this report, we review current recommendations provided by the Centers for Disease Control and Prevention (CDC) and the 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 Clinical and Laboratory Standards Institute on how to test for these infections.

Evaluation of supplemental testing with the Multispot HIV-1/HIV-2 Rapid Test and APTIMA HIV-1 RNA Qualitative Assay to resolve specimens with indeterminate or negative HIV-1 Western blots.

BACKGROUND: The use of Western blot (WB) as a supplemental test after reactive sensitive initial assays can lead to inconclusive or misclassified HIV test results, delaying diagnosis. OBJECTIVE: To determine the proportion of specimens reactive by immunoassay (IA) but indeterminate or negative by WB that could be resolved by alternative supplemental tests recommended under a new HIV diagnostic testing algorithm. STUDY DESIGN: Remnant HIV diagnostic specimens that were reactive on 3rd generation HIV-1/2 IA and either negative or indeterminate by HIV-1 WB from 11 health departments were tested with the Bio-Rad Multispot HIV-1/HIV-2 Rapid Test (Multispot) and the Gen-Probe APTIMA HIV-1 RNA Qualitative Assay (APTIMA). RESULTS: According to the new testing algorithm, 512 (89.8%) specimens were HIV-negative, 55 (9.6%) were HIV-1 positive (including 19 [3.3%] that were acute HIV-1 and 9 [1.6%] that were positive for HIV-1 by Multispot but APTIMA-negative), 2 (0.4%) were HIV-2 positive, and 1 (0.2%) was HIV-positive, type undifferentiated. 47 (21.4%) of the 220 WB-indeterminate and 8 (2.3%) of the 350 WB-negative specimens were HIV-1 positive. CONCLUSION: Applying the new HIV diagnostic algorithm retrospectively to WB-negative and indeterminate specimens, the HIV infection status could be established for nearly all of the specimens. IA-reactive HIV-infected persons with WB-negative results had been previously misclassified as uninfected, and HIV diagnosis was delayed for those with WB-indeterminate specimens. These findings underscore the limitations of the WB to confirm HIV infection after reactive results from contemporary 3rd or 4th generation IAs that can detect HIV antibodies several weeks sooner than the WB.

Relative accuracy of serum, whole blood, and oral fluid HIV tests among Seattle men who have sex with men.

BACKGROUND: Point-of-care (POC) rapid HIV tests have sensitivity during the "window period" comparable only to earliest generation EIAs. To date, it is unclear whether any POC test performs significantly better than others. OBJECTIVE: Compare abilities of POC tests to detect early infection in real time. STUDY DESIGN: Men who have sex with men (MSM) were recruited into a prospective, cross-sectional study at two HIV testing sites and a research clinic. Procedures compared four POC tests: one performed on oral fluids and three on fingerstick whole blood specimens. Specimens from participants with negative POC results were tested by EIA and pooled nucleic acid amplification testing (NAAT). McNemar's exact tests compared numbers of HIV-infected participants detected. RESULTS: Between February 2010 and May 2013, 104 men tested HIV-positive during 2479 visits. Eighty-two participants had concordant reactive POC results, 3 participants had concordant non-reactive POC tests but reactive EIAs, and 8 participants had acute infection. Of 12 participants with discordant POC results, OraQuick ADVANCE Rapid HIV-1/2 Antibody Test performed on oral fluids identified fewer infections than OraQuick performed on fingerstick (p = .005), Uni-Gold Recombigen HIV test (p = .01), and determine HIV-1/2 Ag/Ab combo (p = .005). CONCLUSIONS: These data confirm that oral fluid POC testing detects fewer infections than other methods and is best reserved for circumstances precluding fingerstick or venipuncture. Regardless of specimen type, POC tests failed to identify many HIV-infected MSM in Seattle. In populations with high HIV incidence, the currently approved POC antibody tests are inadequate unless supplemented with p24 antigen tests or NAAT.

Costs and outcomes of laboratory diagnostic algorithms for the detection of HIV.

BACKGROUND: An alternative HIV testing algorithm, designed to improve the detection of acute and early infections and differentiate between HIV-1 and HIV-2 antibodies, has been developed by the Centers for Disease Control and Prevention and the Association of Public Health Laboratories. While it promises greater sensitivity, it also raises concerns about costs. OBJECTIVE: We sought to compare the most commonly used algorithm which was developed in 1989, a third-generation (3G) immunoassay (IA) and Western blot confirmatory test, to a newer algorithm. The new algorithm includes either a 3G or a fourth-generation (4G) initial IA, followed by confirmatory testing with a HIV-1/HIV-2 differentiation IA and, if needed, a nucleic acid amplification test (NAT). STUDY DESIGN: We conducted an analysis of HIV testing costs from the perspective of the laboratory, and classified costs according to IA testing volume. We developed a decision analytic model, populated with cost data from 17 laboratories and published assay performance data, to compare the cost-effectiveness of the testing algorithms for a cohort of 30,000 specimens with a 1% HIV prevalence and 0.1% acute HIV infection prevalence. RESULTS: Costs were lower in high-volume laboratories regardless of testing algorithm. For specimens confirmed positive for HIV antibody, the alternative algorithm (IA, Multispot) was less costly than the current algorithm (IA, WB); however, there was wide variation in reported testing costs. For our cohort, the alternative algorithm initiated with a 3G IA and 4G IA identified 15 and 25 more HIV infections, respectively, than the 1989 algorithm. In medium-volume laboratories, the 1989 algorithm was more costly and less effective than the alternative algorithm with a 3G IA; in high-volume laboratories, the alternative algorithm with 3G IA costs $162 more per infection detected. The alternative algorithm with 4G instead of 3G incurred an additional cost of $14,400 and $4865 in medium- and high-volume labs, respectively. DISCUSSION: HIV testing costs varied with IA testing volumes. The additional cost of 4G over 3G IA might be justified by the additional cases of HIV detected and transmissions averted due to earlier detection. CONCLUSION: The alternative HIV testing algorithm compares favorably to the 1989 algorithm in terms of cost and effectiveness.

Expanding HIV testing: back to the future.

The value of HIV testing has grown in parallel with the development of increasingly effective HIV treatment. Evidence for the substantial reductions in transmission when persons receive antiretroviral therapy creates a new impetus to increase testing and early diagnosis. Models of treatment as prevention--dubbed "test and treat"--give reason for optimism that control and elimination of HIV may now be within reach. This will be possible only with widespread testing, prompt and accurate diagnosis, and universal access to immediate antiviral therapy. Many successful approaches for scaling up testing were pioneered in resource-limited countries before they were adopted by countries in the developed world. The future of HIV testing is changing. Lessons learned from other case-finding initiatives can help chart the course for comparable HIV testing endeavors.