Study reveals promise for New/Improved HIV
testing & Reporting Results on Internet
Early detection hope of S.D. researchers - full text study publication follows below|
By Keith Darce, UNION-TRIBUNE STAFF WRITER
Tuesday, June 15, 2010 at 12:05 a.m.
"Early Test program reported negative test results by using automated Internet and voicemail systems, consistent with the role of new technologies in the prevention of HIV and other sexually transmitted infections (16–25), which were acceptable to clients and had high uptake. Overall, 69% of Early Test clients retrieved their negative NAT results by either Internet or voicemail systems, even though Early Test staff told them that they would be contacted if their NAT results required follow-up and they all had already received a negative antibody result by RT.,,,,,...The identification of persons recently infected with HIV (that is, acute and early HIV infection) by using NAT has been proposed and evaluated as a way to reduce the incidence of HIV infection; however, its utility may be limited by costs.......Between February 2007 and January 2009, the Early Test program found 15 cases of HIV infection that would have been missed by HIV antibody testing alone, increasing case yield by 23%" Annals of Internal Medicine June 2010
* Community-based HIV testing programs generally use only HIV antibody testing. Nucleic acid testing (NAT) can detect the presence of HIV earlier than antibody testing.
* In an HIV testing program that incorporated NAT and automated reporting of negative NAT results, nearly one quarter of persons with identified cases had positive results only by NAT testing. More than two thirds of clients with negative NAT results retrieved them via the Internet or voicemail.
* The study focused on urban clinics serving men who have sex with men. Findings may not be applicable to populations with lower HIV prevalence or less use of automated technologies.
* Addition of NAT to HIV antibody testing in community-based programs may significantly improve case yield. Automated reporting of negative results may prove to be an acceptable alternative to face-to-face reporting.
The evolution of AIDS from a deadly disease shrouded in fear to a largely manageable condition took another step forward Monday, when San Diego researchers unveiled results of a study looking at an early-detection method for the virus that causes the illness.
The report's authors said a rarely used blood test can spot HIV weeks before the body recognizes the infection. They recommended that it be offered along with the more common screening method to people at high risk of contracting the virus, including gay men, intravenous drug users and people with multiple sex partners.
Among the 3,151 participants in a two-year study, the blood test identified HIV in 15 individuals who had falsely tested negative with the traditional saliva swab procedure.
False negative results occur in as much as 1 percent of those who take the swab test, which pinpoints antibodies produced by the immune system in response to infection. It can take as long as three months for the body to begin producing enough antibodies to trigger a positive reading.
During that lag time, people can unknowingly spread HIV through unsafe sex and miss early treatments that could improve their health in the long run, said Dr. Sheldon Morris, an AIDS researcher at the University of California San Diego's Antiviral Research Center in Hillcrest.
Morris was lead author of the HIV-testing report, which appeared Monday in the journal Annals of Internal Medicine. His colleagues included other researchers from UCSD and San Diego County's HIV, STD and Hepatitis Branch.
"If people got an antibody test alone and were told they weren't infected when they were, they could be a strong infection risk until they get tested again, which according to guidelines could be six to 12 months later," Morris said.
The latest findings reinforce similar conclusions from a 2005 study led by scientists at the University of North Carolina. Those researchers administered the early-detection blood test to a much larger sampling of people.
Participants in the San Diego study whose blood tested negative could get their results in person, through an automated telephone system or by logging on to a secured website. About 65 percent of those who sought their results used the automated options.
Morris said the pattern demonstrates a shift in attitudes about AIDS. The illness once was viewed as a death sentence that needed in-person counseling to deal with issues such as shame and secrecy. But advances in detection and treatment have turned it into a chronic, controllable condition for most patients - not unlike diabetes.
"HIV is not as mysterious as it once was," Morris said.
The early-detection blood test, which homes in on nucleic acid RNA molecules produced by the virus, has been used to screen most of the nation's blood donation supply since 2002, according to its maker, Gen-Probe of San Diego.
The FDA approved the test for use as an HIV diagnostic tool in late 2006, but its cost - as high as $100 - and more complicated administration have helped discourage widespread use, said Rowena Johnston, vice president and research director of the New York-based international HIV/AIDS research foundation known as AMFAR.
Samples for the blood test are obtained through finger pricks and must be sent to a laboratory, which can take up to two weeks to return results.
"The reason the antibody test is (widely) used is because of low cost and convenience," Johnston said. The saliva swab method can produce a reading within a few minutes.
But identifying people with HIV within a few days or weeks of infection has become a public health imperative, in part because the virus level tends to be highest during the early infection stage - making transmission to others more likely, she said.
"This really is a key to preventing HIV transmission," Johnston said.
Because of the blood test's cost, health experts said, it probably isn't practical to offer the higher-level screening to the general population. It makes more sense to focus on high-risk HIV groups because they record larger numbers of false-negative antibody test results.
In the San Diego study, participants were recruited from several HIV testing sites in the region, including those run by UCSD, the county and the Lesbian, Gay, Bisexual, Transgender Community Center.
Each participant was given the saliva swab test, and then blood samples were taken from those who tested negative. The samples were sent to labs in San Diego and Emeryville in the Bay Area, where they were analyzed for HIV nucleic acid. Patients who tested positive for HIV after the blood analysis received the results from clinic staffers within a week.
Morris said the blood test is sensitive enough to detect the virus components within 10 days of infection.
"I think the time is coming where we will have to adopt a strategy for earlier (HIV) detection," he said. "If you have a testing site with a high-risk prevalence, then you probably should be running this test on all of their samples" that tested negative for virus antibodies.
Annals of Internal Medicine
Evaluation of an HIV Nucleic Acid Testing Program With Automated Internet and Voicemail Systems to Deliver Results
1. Sheldon R. Morris, MD, MPH;
2. Susan J. Little, MD;
3. Terry Cunningham, MAOM;
4. Richard S. Garfein, PhD, MPH;
5. Douglas D. Richman, MD; and
6. Davey M. Smith, MD, MAS
From the University of California, San Diego, San Diego Health and Human Services, and Veterans Affairs San Diego Healthcare System, San Diego, California.
Background: Nucleic acid testing (NAT) in routine HIV testing programs can increase the detection of infected individuals, but the most effective implementation of NAT remains unclear.
Objective: To determine how many HIV cases can be identified with NAT and how many persons can be contacted, to identify predictors of acute and early HIV infection cases, and to test reporting of negative results by automated Internet and voicemail systems.
Design: Prospective study.
Setting: San Diego County, California.
Participants: Persons seeking HIV testing.
Measurements: Rates and predictors of HIV infection by stage, notification of positive NAT results, use of automated Internet or voicemail systems to access negative NAT results, and estimated HIV infections prevented.
Results: Of 3151 persons tested, 79 had newly diagnosed cases of HIV: 64 had positive results from rapid HIV test, and 15 had positive results only by NAT (that is, NAT increased the HIV detection yield by 23%). Of all HIV infections, 44% (in 35 persons) were in the acute and early stages. Most participants (56%) and persons with HIV (91%) were men who have sex with men (MSM). All persons with NAT-positive results were notified within 1 week. Of all 3070 uninfected patients, 2105 (69%) retrieved their negative NAT results, with 1358 using the Internet system. After adjustment for covariates, persons reporting MSM behavior, higher incomes, younger ages, no testing at substance abuse rehabilitation centers, no recent syphilis, and no methamphetamine use were more likely to access negative NAT results by either Internet or voicemail systems.
Limitation: Findings may not be generalizable to other populations and testing programs.
Conclusion: Nucleic acid testing programs that include automated systems for result reporting can increase case yield, especially in settings that cater to MSM.
Primary Funding Source: California HIV/AIDS Research Program and the National Institutes of Health.
Despite decades of prevention efforts in the United States, the incidence rate of HIV has remained stable (1). Because the earliest stages of HIV infection represent a period of maximum infectiousness related to high HIV load, accurate detection of HIV infection during acute and early stages may be critical to control the HIV epidemic (2–4). To protect the U.S. blood supply, blood donors are screened for acute HIV infection by nucleic acid testing (NAT) (5), which can detect infection approximately 12 days before antibody positivity (2). Extending the use of NAT to routine HIV testing programs might help decrease the HIV incidence rate by identifying persons with acute infection that would otherwise be missed by antibody screening. Although this concept was effective in pilot studies in the United States and Africa, it needs to be broadly implemented in routine HIV testing programs (6–9). We evaluated an HIV testing program that incorporated NAT, automated reporting of negative results, and direct contact tracing for positive results. Specific outcomes measured included additional yield of HIV cases, characteristics of persons with acute and early HIV infection, and uptake of automated reporting of negative HIV results.
The identification of persons recently infected with HIV (that is, acute and early HIV infection) by using NAT has been proposed and evaluated as a way to reduce the incidence of HIV infection; however, its utility may be limited by costs. The largest study of HIV NAT (6), performed in North Carolina, reported a 3.3% increase in the state budget for HIV-related services when HIV NAT was added to routine HIV screening. This translated to an additional $3.63 per person tested and $17 515 per HIV infection that would not otherwise be diagnosed. We built on these and other pioneering efforts (8, 9) by evaluating the effectiveness of an HIV testing program (the Early Test) that incorporated NAT into an HIV testing platform to identify clients who have acute and early HIV infection. Between February 2007 and January 2009, the Early Test program found 15 cases of HIV infection that would have been missed by HIV antibody testing alone, increasing case yield by 23%. The cost of finding these additional HIV cases in the Early Test program was $10 248 per case, including the costs of building and operating the Internet and voicemail systems. Although the North Carolina study used a pooled NAT platform to reduce costs and the Early Test program used a nonpooled NAT platform, the North Carolina program cost about $7000 more per additional HIV case identified than the Early Test program. This cost difference probably reflects differing laboratory and reporting costs and that the Early Test program operated in a relatively higher-risk setting (HIV prevalence of testing population for the North Carolina program vs. Early Test program, 0.6% vs. 2.5%) (6).
A major advance in HIV testing has been the adoption of RT, in which the follow-up visit can be eliminated. Loss to follow-up is prevented, and instant posttest counseling is provided to patients (4, 11–13). However, not all HIV testing programs offer RT, and programs that use NAT to detect acute HIV do not have an available point-of-care NAT test (8, 9, 14, 15). Therefore, the Early Test program reported negative test results by using automated Internet and voicemail systems, consistent with the role of new technologies in the prevention of HIV and other sexually transmitted infections (16–25), which were acceptable to clients and had high uptake. Overall, 69% of Early Test clients retrieved their negative NAT results by either Internet or voicemail systems, even though Early Test staff told them that they would be contacted if their NAT results required follow-up and they all had already received a negative antibody result by RT. Barriers to retrieving HIV-negative results included recent history of syphilis, methamphetamine use, and drug rehabilitation-characteristics that may signify reduced health care–seeking behavior (26–29). Further studies are needed to learn whether structural (that is, access to computers) versus individual (that is, motivation or self-efficacy) factors influence access of results. The demographic factors of age older than 45 years, African-American race, and lower income (all of which have been previously associated with less Internet use [30, 31]) were also barriers to Internet use and retrieving NAT results. In addition, some clients accessed their results multiple times, perhaps as a way to gain repeated reassurance, which would not be possible in a standard face-to-face posttest counseling session. Of note, we did not report HIV-positive results on the automated systems, and these results were provided only by a trained counselor in a face-to-face session, as recommended by the Centers for Disease Control and Prevention (4).
Another advance in HIV testing has been fourth-generation HIV assays, which include an antibody assay with detection of P24 antigen and can identify 62% to 94% of acute infections that would otherwise be detected only by NAT (32–34). Fourth-generation HIV assays will probably still miss some very early HIV infections when the infection has a low initial viral load (that is, <25 000 HIV RNA copies/mL) or when testing occurs during the window of infection between loss of P24 antigen in the blood and emergence of a positive antibody test result (32, 34, 35). Testing persons during this very early period who have corresponding low viral loads may also cause cases to be missed when pooled NAT approaches are used, which is done to reduce overall testing costs (6). In fact, the nonpooling NAT strategy of the Early Test detected some very acute HIV infections (n = 5) with initial low viral loads (1340, 1200, 544, 540, and <50 copies/mL) and that may not have been detected by pooled NAT or fourth-generation HIV assays. A comparative analysis of pooled and nonpooled NAT programs and fourth-generation HIV assays will probably be needed to better evaluate the cost and effectiveness of each strategy, and these outcomes may also differ depending on the testing setting (that is, high-risk vs. low-risk groups). Testing algorithms that incorporate more sensitive assays, like fourth-generation HIV assays or NAT, should become the standard of care because they are more effective at diagnosing HIV cases compared with oral RT alone (36).
A potential limitation of this study is whether our findings can be generalized to other populations and testing programs. San Diego is similar to many urban settings, particularly in the western United States, where MSM are the main risk group for HIV. The behavior reported in our study was consistent with population surveys of MSM in California (37, 38). Other urban-based HIV testing programs that integrated HIV NAT for high-risk populations should see similar results. Despite these limitations, this study should motivate further research into the use of NAT in HIV testing programs with measurement of cost-effectiveness and prevention of HIV transmission.
HIV Infections Detected
Data were cut off on 20 January 2009 and analyzed for all patients who been evaluated between 6 February 2007 and 1 January 2009. In this period, the total number of Early Test clients was 3344, and 3151 of these persons had complete data entry for test results, demographic characteristics, and risk behaviors. In these 3151 patients, 814 did not report income, and 85 had incomplete demographic information: 78 did not report ethnicity or race, 4 did not report age, and 4 did not report sex. Most Early Test clients were men (n = 2563), and most of these were MSM (n = 1774) (Table 1).
In these 3151 patients, 79 (2.5% [CI, 2.0% to 3.1%]) had newly diagnosed HIV infection. Of these 79 patients, 35 (44%) had acute and early HIV infection, and 44 (56%) had chronic HIV infection. Of the 35 patients with acute and early HIV, 15 (19% of all patients with HIV) had acute HIV infection (that is, positive NAT and negative RT results), and 20 had early HIV infection (positive RT and negative detuned EIA results). Use of nonpooled HIV NAT increased the overall yield of newly diagnosed HIV cases by 23%. The median viral load of the acute HIV infection detected was 127 000 copies/mL, with a range of less than 50 to 7 440 000 copies/mL, and the 5 cases with the lowest viral loads had 1340 or fewer copies/mL. The viral load of 1 patient with acute HIV infection was initially undetectable but reached the millions of copies/mL by the next week. One additional person who had positive NAT results initially but negative RT results later received a diagnosis of chronic infection on the basis of history, full evolution of the Western blot, positive serum EIA result, positive detuned EIA result, and an undetectable viral load. This person was a heterosexual man who tested with his female partner, who had positive RT and positive detuned EIA results. We suspected that these persons knew their HIV status and were receiving antiretroviral medication before testing and thus were not counted as having newly diagnosed HIV infection.
We found that MSM had the highest rate of overall HIV infection (4.1% infected of 1774 MSM [CI, 3.2% to 5.1%]) and NAT result positivity among persons with negative RT results (0.9% [CI, 0.5% to 1.4%]). A total of 1381 MSM enrolled while data were being collected on sexual risk factors in the previous year, with 1240 reporting insertive or receptive anal sex and 1369 reporting the number of male sexual partners. In the 1240 patients with responses for the previous year and data for all covariates, acute and early HIV infection was correlated in univariate analysis with a self-reported recent diagnosis of syphilis (P = 0.044), methamphetamine use (P = 0.087), and having 10 or more sexual partners in the past year (P = 0.031). After exact logistic regression, the strength of these associations became less significant, with an adjusted odds ratio for an association between acute and early HIV infection and syphilis of 3.8 (CI, 0.7 to 13.9) and between acute and early HIV infection and 10 or more male sexual partners of 2.8 (CI, 1.0 to 7.8). Other factors, such as unprotected anal sex, drug use, and race and ethnicity, were not significantly associated with acute and early HIV infection (Table 2).
During this 23-month study, the cost of laboratory and technician time for NAT was $52 631, the cost of setting up the Web site that integrated data collection and of mediating Internet results was approximately $100 000, and the cost of the voicemail system was $11 500. Based on the total of these costs ($164 131), the estimated cost per additional HIV case found by the NAT program was $10 258.
Predictors of Receiving NAT Results
Of the 3070 clients who had negative results for HIV by RT and NAT, 2105 (69%) accessed their negative NAT results by either the Internet or the voicemail system (Table 3). The Internet was the first choice for 1358 clients (65%). However, 94 clients who first accessed their results by voicemail also accessed their results via the Internet later. Most people who accessed their results did so a median of 1 time but ranged up to 99 times, and repeated access was usually done via the Internet. An analysis of the predictors of retrieving negative NAT results was performed in 2264 patients who had data for all predictors. After adjustment for covariates, the retrieval of negative NAT results by either Internet or voicemail was more likely in persons reporting MSM behavior, higher incomes, younger ages, no residence at substance abuse rehabilitation centers, no recent syphilis diagnosis, and no methamphetamine use (Table 4). A similar analysis was also performed in 1631 persons who retrieved their result and had all data elements to predict use of the Internet rather than voicemail. Internet use was more likely in persons reporting MSM behavior, income greater than $1000 a month, and age younger than 45 years. African-American clients were the least likely to use the Internet for retrieval of negative NAT results compared with all other racial and ethnic groups. Intravenous drug users and patients attending inpatient rehabilitation centers were both less likely to use the Internet.
ll clients with positive NAT results were contacted by using information provided at the initial testing within 30 minutes to 1 week after their NAT results were received. Most clients with positive results received these results within 24 hours; 100% of these clients were referred to HIV care, and they all attended their first visit.
Client Satisfaction With the Early Test and Internet Reporting
Starting from April 2008, the Internet-based survey was completed by 239 clients who retrieved their negative NAT results on the Internet system during the availability of the survey, and 235 clients completed demographic questions on sex and sexual orientation. Of these 235 respondents, 208 were men and 178 reported having a male sexual partner in the past month. Of the 235 respondents, 232 (98.7%) said it was "very important" to have testing available for acute and early HIV infection, 161 (69%) said they had already referred someone else to the Early Test program, and all but 1 (99.5%) said they would refer someone in the future. Consistent with the survey being online, 219 (93%) of respondents reported using the Internet on a daily basis, and 204 (87%) reported that they were "comfortable" or "very comfortable" with retrieving their results on the Internet.
Study Design, Setting, and Participants
This was a prospective study of an HIV testing program (the Early Test; http://theearlytest.ucsd.edu) that was designed to identify and stage HIV infection. Starting in February 2007, the Early Test program operated at HIV testing sites in San Diego County, including HIV testing sites for men who have sex with men (MSM) at the Lesbian, Gay, Bisexual, Transgender Center and the Gay Men's Health Clinic; the San Diego County Health Department; the University of California, San Diego (UCSD), Antiviral Research Center; and substance abuse treatment centers. During the study, the only social marketing was distribution of flyers at gay-oriented venues and printing advertisements in gay-oriented publications. Sites were instructed to offer study enrollment to anyone who presented for HIV testing. The staff at each site, after protocol training by UCSD Early Test personnel, obtained consent and performed procedures. Persons 18 years or older who presented for routine HIV testing and were able to give informed consent were offered enrollment in the Early Test program. From April 2008, participants were also offered an Internet-based survey after online retrieval of negative NAT results. Analyses represent testing until 1 January 2009. The study was approved by a local program for the protection of human research subjects.
The Figure summarizes enrollment procedures. At enrollment, participants were provided standard HIV risk-reduction counseling, data were collected on reported HIV risk behaviors, point-of-care rapid HIV antibody testing (RT) was performed (Oraquick Advance rapid HIV, OraSure Technologies, Bethlehem, Pennsylvania), and RT results and posttest counseling were given by trained personnel. If the RT result was positive, a blood sample was collected and sent for confirmation by immunofluorescent assay (Fluorognost, Sanochemia, Stamford, Connecticut), viral load testing (Cobas Amplicor HIV-1 test, Roche Molecular Systems, Pleasanton, California), and a detuned HIV enzyme-linked immunoassay (EIA) (Vironostika LS EIA, bioMerieux, Durham, North Carolina) from February 2007 to August 2008 and Vitros LS EIA (Ortho-Clinical Diagnostics, High Wycombe, United Kingdom) from August 2008 to January 2009. If the RT result was negative, blood plasma was collected and sent to the American Red Cross for NAT by Procleix HIV-1/HCV Assay (Chiron, Emeryville, California, and Genprobe, San Diego, California) without pooling. We encoded NAT results by a unique identification number and sent them to Early Test staff by secure electronic data transfer. Patients with a negative RT result were told that if they were not contacted by Early Test staff within 2 weeks, they could call the Early Test voicemail number or log in to the Early Test Web site to retrieve their NAT results (only negative test results were posted to these systems). Patients were guided to enter a personal identification number twice to access an anonymous report of negative NAT status. We never communicated HIV antibody or positive NAT results over the Internet or through a voicemail system. If the NAT result was positive for HIV, then confirmatory testing was initiated with HIV viral load (Cobas Amplicor HIV-1 test). The patient was contacted by using information provided at the time of initial testing.
Data Collection and Analysis
Patients who were not offered the Early Test or who declined participation were not available for data analysis. During the pretest assessment, collected data included contact information, demographic characteristics, income, exposure risk categories, sexual behavior, recent diagnosis of sexually transmitted infections, and drug use. Risk behavior measures changed during the study because of changes in state reporting requirements. From February to October 2007, clients reported risk over the previous 3 months. From November to December 2007, clients reported risk since their last HIV test. From January 2008 to January 2009, clients reported risk over the past year. Risk factors for sexually transmitted infections and drug use were defined as being reported "any time" versus "none" or "not reported." Number of sexual partners and condom use with anal sex were defined only for those who reported behavior in the past year. The Internet-based survey was available starting in April 2008 for clients retrieving their negative NAT results. Main questions about the Internet results system asked about the importance of the Early Test for the community (rated "not very important" to "very important"), personal Internet use (less than once a month to daily), and whether participants would refer someone to the Early Test program.
We analyzed HIV case finding by reported HIV risk, sex, ethnicity, and estimated duration of infection. Stage of HIV infection at diagnosis was defined as acute HIV infection when NAT results were positive and RT results were negative, consistent with an infection within 10 days (95% CI, 7 to 14 days) of testing (2); as early HIV infection when the RT results were positive with detuned EIA results, consistent with infection of less than 133 days (CI, 113 to 160 days) (10); and as chronic HIV infection when the RT results were positive with detuned EIA results, consistent with infection of greater than 133 days (10).
We analyzed persons who reported their sex and sexual orientation. Univariate analyses used the chi-square test for tables and dichotomous variables and univariate logistic regression for ordinal variables. The Fisher exact test was used for analyses with fewer than 5 observations in any 1 cell. For risk factors associated with acute and early HIV infection in MSM, variables known to be possible risk factors for HIV acquisition were analyzed in SAS, version 9 (SAS Institute, Cary, North Carolina), with exact multivariate logistic regression without selection methods by using LogXact procs (Cytel Software, Cambridge, Massachusetts) for SAS to accommodate the smaller number of outcomes. This methodology restricts use of continuous covariates with many response levels. To minimize the number of covariates for the exact methods, we condensed some risk factors to clinically relevant binary outcomes for age younger than 45 years, white non-Hispanic race, and 10 or more sexual partners. Adjusted odds ratios were calculated for correlates with 95% CIs. We used SAS to do multivariate analysis without selection for predictors of not retrieving NAT results in logistic regression without selection. Response data from the satisfaction survey were analyzed by using descriptive statistics.
The cost of the program was estimated for the additional costs of the NAT, the additional laboratory staff, and the development of a functional Web site and maintenance of a voicemail system. The total cost of the program was then divided by the number of HIV cases found by NAT only to calculate the cost per additional HIV case identified by NAT.
Role of the Funding Source
This project was funded by the California HIV/AIDS Research Program and the National Institutes of Health. The funding sources did not have a role in the design, conduct, or analysis of the project.