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Original Investigation |

Detecting Acute Human Immunodeficiency Virus Infection Using 3 Different Screening Immunoassays and Nucleic Acid Amplification Testing for Human Immunodeficiency Virus RNA, 2006-2008 FREE

Pragna Patel, MD, MPH; Duncan Mackellar, MA, MPH; Pat Simmons, BS; Apurva Uniyal, MA; Kathleen Gallagher, MPH; Berry Bennett, MPH; Timothy J. Sullivan, BS; Alexis Kowalski, MPH; Monica M. Parker, PhD; Marlene LaLota, MPH; Peter Kerndt, MD, MPH; Patrick S. Sullivan, DVM, PhD; Centers for Disease Control and Prevention Acute HIV Infection Study Group
[+] Author Affiliations

Author Affiliations: Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia (Dr Patel and Mr Mackeller); Bureau of HIV/AIDS, Florida Department of Health, Tallahassee (Mss Simmons and LaLota); Sexually Transmitted Disease Program, Los Angeles Department of Health Services, Los Angeles, California (Ms Uniyal and Dr Kerndt); Bureau of Sexually Transmitted Disease Control, New York City Department of Health and Mental Hygiene, New York, New York (Mss Gallagher and Kowalski); Retrovirology Section, Florida Bureau of Laboratories, Jacksonville (Mr Bennett); Wadsworth Center, New York State Department of Health, Albany (Mr T. J. Sullivan and Dr Parker); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia (Dr P. S. Sullivan).


Arch Intern Med. 2010;170(1):66-74. doi:10.1001/archinternmed.2009.445.
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Published online

Background  The yield of nucleic acid amplification testing (NAAT) after routine screening for human immunodeficiency virus (HIV) antibody to detect acute HIV infection (AHI) may vary with different HIV-antibody assays.

Methods  From April 24, 2006, through March 28, 2008, patients underwent routine HIV-antibody screening using a first-generation assay at 14 county sexually transmitted disease (STD) clinics and 1 community clinic serving homosexual patients in Los Angeles; using a second-generation rapid test at 3 municipal STD clinics in New York; and using a third-generation assay at 80 public health clinics in Florida. To identify AHI, seronegative specimens were pooled for NAAT, followed by individual NAAT of specimens with positive findings. All AHI samples screened by first- and second-generation assays also underwent third-generation testing.

Results  We screened 37 012 persons using NAAT after first-generation testing; 35 AHIs were identified, increasing HIV case detection by 8.2%. After a second-generation rapid test, 6547 persons underwent NAAT; 7 AHIs were identified, increasing HIV case detection by 24.1%. After third-generation testing, 54 948 persons underwent NAAT; 12 AHI cases were identified, increasing HIV case detection by 1.4%. Overall, pooled NAAT after negative third-generation test results detected 26 AHI cases, increasing HIV case detection by 2.2%. Most of the AHI cases from Los Angeles (26 of 35 [74%]) were identified at the community clinic where NAAT after third-generation testing increased HIV case detection by 11.9%.

Conclusions  Pooled NAAT after third-generation testing increases HIV case detection, especially in venues of high HIV seropositivity. Therefore, targeted AHI screening using pooled NAAT after third-generation testing may be most effective, warranting a cost-benefit analysis.

Figures in this Article

Acute human immunodeficiency virus (HIV) infection (AHI) represents the stage of the disease in which viral replication and shedding occurs before detectable antibody appears.1 During this time, viral load peaks in blood and genital secretions,25 resulting in individuals who are highly infectious and are often unaware of their HIV status.6 Individuals with AHI may have recently engaged in high-risk behaviors and have concurrent relationships.716 Several models have suggested that a disproportionate number—up to 50%—of new HIV infections are acquired by onward transmission from persons with AHI.1621 Because most HIV-infected persons take measures to reduce their risk of further transmission after they learn of their infection,2225identifying individuals during AHI affords an important opportunity for HIV prevention. Nonetheless, diagnosis of AHI is challenging and requires modification of standard HIV testing algorithms.

The following 2 types of conventional HIV-antibody screening tests are approved for use in the United States: (1) first- and second-generation IgG-sensitive indirect enzyme immunoassays (EIAs) that detect antibody to viral lysate and recombinant or synthetic peptide antigens, respectively, and (2) third-generation IgM- and IgG-sensitive EIAs that use an antigen-sandwich format, increasing their ability to detect all HIV antibody isotypes.1,26 First-generation HIV-1 EIAs are no longer available for use in the United States. Because IgM is usually expressed before IgG in response to infection, third-generation immunoassays are able to identify persons sooner in the course of their infection compared with earlier-generation immunoassays. Because the p24 antigen, a major core HIV protein, can be detected earlier than HIV antibody, fourth-generation combination immunoassays that detect HIV antibody (IgM/IgG) and p24 antigen can identify infection even sooner than third-generation immunoassays.26 However, fourth-generation immunoassays are not yet available in the United States.

Because conventional HIV assays test for the presence of HIV antibodies, there exists a window during which a person will have negative test results for HIV antibody despite the presence of infection27,28 (Figure 1). Persons with AHI can be identified using nucleic acid amplification testing (NAAT) to detect the presence of HIV RNA during this window period.29 Pooled NAAT, in which specimens are pooled and then tested, is a strategy that has been used routinely for blood-donor screening.29 Nucleic acid amplification testing is predicted to detect HIV infection approximately 45 days earlier than first-generation EIAs, 32 days sooner than second-generation EIAs, 11 days sooner than third-generation EIAs, and 6 days sooner than fourth-generation EIAs27 (Figure 1).

Place holder to copy figure label and caption
Figure 1.

Window of detection of human immunodeficiency virus (HIV) markers early in HIV infection and window period of different enzyme immunoassays compared with nucleic acid amplification testing (NAAT) for HIV RNA. EIA indicates enzyme immunoassay. Data from Fiebig et al27; the figure was adapted from a graphic courtesy of Steven Kleinman, MD.

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Several studies have shown that AHI detection using pooled NAAT after HIV-antibody screening is feasible in public health settings.3035 Although the yield of pooled NAAT will ultimately depend on the sensitivity during seroconversion of the screening immunoassay used,27 all of the previous studies3035 examined the yield of pooled NAAT after relatively insensitive immunoassays (Table 1). The yield of NAAT should be lower when more sensitive screening immunoassays are used. Screening with a third- or fourth-generation assay may have detected nearly 50% to 75% of the HIV-infected persons who had negative test results of a first- or second-generation assay.3638 To assess the feasibility and yield of pooled NAAT relative to first-, second-, and third-generation HIV-antibody screening assays, we implemented AHI screening in 3 areas of historically high HIV prevalence in the United States. To assess the potential yield of fourth-generation screening for AHI detection, we retrospectively tested an unlinked, anonymous, blinded panel of AHI, HIV-positive and HIV-negative specimens with a fourth-generation assay that is used worldwide.

Table Graphic Jump LocationTable 1. Summary of Studies That Have Reported Acute HIV Case Detection Using Pooled NAAT in the United States
STUDY DESIGN

We conducted an observational study to evaluate several strategies for AHI detection in Los Angeles, New York, and Florida. The primary objective was to evaluate the yield of pooled NAAT after first-, second-, and third-generation HIV-antibody screening. Additional objectives were to evaluate the yield of individual NAAT on repeatedly reactive (RR) EIA specimens, timely reporting of NAAT results and partner notification, and the sensitivity of fourth-generation assays for AHI detection.

STUDY POPULATION

From April 24, 2006, to March 28, 2008, all persons who consented to HIV testing, including NAAT, at 14 county sexually transmitted disease (STD) clinics and 1 community clinic for homosexual patients in Los Angeles, 3 health department STD clinics in New York, and approximately 80 public health clinics in 4 Florida counties participated in this study. In 2007, the prevalence of HIV was 0.6% at the Los Angeles STD clinics and 3.5% at the community clinic. In 2007, all 3 New York STD clinics had an average HIV positivity of more than 1%. In 2007, HIV positivity rates in the 4 Florida counties were 1.3% for Duval, 2.3% for Hillsborough, 2.3% for Orange, and 1.0% for Pinellas.

TESTING PROTOCOL

Plasma specimens were collected from all consenting patients at the study sites. All persons underwent initial screening for HIV antibodies; however, each project area used a different EIA. Florida used a third-generation assay (Genetic Systems HIV 1/2 Plus O; Bio-Rad Laboratories, Redmond, Washington) and, in a few study sites, a second-generation rapid test (RT) on fingerstick specimens (OraQuick; Epitope Diagnostics Inc, San Diego, California). New York used a second-generation RT (OraQuick Advance; Epitope Diagnostics Inc) on oral fluid specimens, and Los Angeles used a first-generation assay (Vironostika HIV-1 Microelisa System; bioMerieux, Inc, Durham, North Carolina). All specimens from New York and Los Angeles were subsequently tested with the third-generation assay. We did not conduct incidence testing with the BED assay or less-sensitive/more-sensitive immunoassays.

All persons who presented to study sites in Los Angeles and Florida consented to HIV screening, including NAAT, using their standard HIV testing consent forms. The New York sites used a separate consent for NAAT because persons underwent screening using an RT that provided results on the same day; the consent procedure included an explanation of the window period and AHI. Persons with negative RT results were counseled that they may still be infected with HIV if they underwent testing during the window period.

All specimens with EIA-negative findings were sent to the corresponding study laboratory for pooled NAAT using a qualitative HIV RNA assay (APTIMA HIV-1 RNA; Gen-Probe Inc, San Diego) in a 1-stage 16:1 pooling scheme (an absolute lower limit of detection of 30 copies/mL39 permits detection of individual specimens with ≥1070 copies/mL in a master pool with 1:16 dilution40). The specimens from Los Angeles and New York underwent testing at the Wadsworth Center of the New York State Department of Health, and specimens from Florida were tested at the Florida Bureau of Laboratories. All pools with NAAT-positive results underwent retesting and, if results were repeatedly positive, the pool was deconstructed and each individual specimen underwent NAAT. All individual specimens with NAAT-positive findings underwent retesting in duplicate and confirmation with viral load quantification (Versant HIV-1 RNA 3.0 assay; Siemens Healthcare Diagnostics, Malvern, Pennsylvania) before they were reported to study sites as being NAAT positive. All specimens with EIA-RR/Western blot (WB)–indeterminate and EIA-RR/WB-negative results were tested with NAAT individually; those with NAAT-positive results were confirmed with viral load quantification (Figure 2). If the viral load was undetectable, follow-up testing was conducted to resolve the discrepant test results.

Place holder to copy figure label and caption
Figure 2.

Human immunodeficiency virus (HIV) screening algorithm with pooled nucleic acid amplification testing (NAAT) for the Centers for Disease Control and Prevention Acute HIV Infection Study, 2006-2008. EIA indicates enzyme immunoassay. The proprietary information on the EIAs and APTIMA HIV-1 Assay is given in the “Testing Protocol” subsection of the “Methods” section. *Positive pools and individual specimens underwent testing in duplicate for suspected acute/primary HIV infection.39 †Persons with specimens with positive NAAT results but an undetectable viral load underwent follow-up testing to resolve discrepant results.

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AHI CASE DEFINITION

Based on the initial screening results, all persons with EIA-negative/NAAT-positive results, EIA-RR/WB-indeterminate/NAAT-positive results, and EIA-RR/WB-negative/NAAT-positive results and who had detectable viral loads were considered presumptive AHI cases; we included persons with WB-negative or -indeterminate results in our case definition because they were most likely in the window period. Persons with presumptive AHI had specimens drawn for follow-up confirmatory testing on the day they received their test results. Follow-up plasma specimens underwent EIA, WB, individual NAAT, and viral load testing. After this second confirmatory test, patients with NAAT-positive results who continued to have negative or indeterminate WB results were followed up every 2 weeks for up to 12 weeks to confirm HIV seroconversion.

We obtained demographic and risk-factor data on all persons who consented to HIV testing from routinely collected, program-specific HIV counseling and testing forms.

FIELD PROTOCOL

Disease intervention specialists, public health workers who are responsible for finding and counseling people with STDs and their contacts, were specially trained to notify presumptive AHI cases of their results and the need for confirmatory testing and to refer persons to care and partner notification services. Sexual or needle-sharing partners of AHI cases were notified as soon as possible and offered HIV testing using the same study protocol. We did not collect information about postexposure prophylaxis.

EVALUATION OF FOURTH-GENERATION ASSAY

To evaluate fourth-generation screening for AHI detection, an unlinked, anonymous, blinded panel of 38 AHI, 43 HIV-positive, and 119 HIV-negative specimens was sent to Abbott Diagnostics, Abbott Park, Illinois, for testing with the Architect HIV Ag/Ab Combo assay (List 4J27; Abbott Diagnostics, Wiesbaden, Germany; available for sale outside the United States only). The 38 AHI specimens were from persons with documented seroconversion and included initial and follow-up specimens from the same individual. Because this assay is not approved by the US Food and Drug Administration, this evaluation was conducted retrospectively and results were not reported to participants; however, it was expected that fourth-generation assay results would not alter the interpretation of participants' HIV test results.

ANALYSIS

Presumptive AHI was defined as in the “AHI Case Definition” subsection. Persons with EIA-RR/WB-positive results, regardless of the NAAT result, were considered established cases of HIV infection. For each and all project areas combined, we report the number and percentage of specimens that were received for screening, specimens undergoing testing with NAAT, persons with presumptive AHI, and persons with AHI with documented seroconversion. In addition, we calculated the increase in HIV case detection attributed to NAAT. Descriptive and univariate analyses were conducted using commercially available software (SAS, version 9.2; SAS Institute Inc, Cary, North Carolina). Test performance characteristics, such as specificity, were calculated using an open-source software program (OpenEpi, version 2.2.1; Emory Rollins School of Public Health).4143

HUMAN SUBJECTS PROTECTIONS

The Centers for Disease Control and Prevention (CDC) and local institutional review board approvals were obtained by all 3 project areas. The evaluation of the fourth-generation assay was granted a nonresearch determination per CDC guidelines.

STUDY POPULATION

From April 24, 2006, through March 28, 2008, 99 111 persons underwent testing using an antibody plus NAAT algorithm (Figure 2) in Los Angeles, New York, and Florida. Of all 99 111 persons who underwent screening, the median age was 26 (range, 14-111) years; 52.0% were female, 37.4% were black non-Hispanic, and 68.3% were self-identified heterosexuals. Of the 9832 participants who identified themselves as men who have sex with men, 71.3% underwent screening in Los Angeles (Table 2).

Table Graphic Jump LocationTable 2. Characteristics of CDC Acute HIV Infection Study Population and Project Areas, 2006-2008a
CASE IDENTIFICATION

In Los Angeles, from May 1, 2006, through February 29, 2008, 37 012 specimens were screened for HIV. Of these, 36 512 (98.6%) had EIA-negative/NAAT-negative results, and 424 (1.1%) had EIA-RR/WB-positive results. Of 36 individuals who met the AHI case definition, 1 had a false-positive NAAT result. Adding NAAT to first-generation EIA screening in Los Angeles increased HIV case detection by 8.2%. Of the 35 persons with AHI, 17 (48.6%) were detected with the third-generation assay, decreasing the yield of NAAT to 4.1% (Table 3).

Table Graphic Jump LocationTable 3. CDC Acute HIV Infection Study Results by Project Area, 2006-2008a

Twenty-six of the Los Angeles AHI cases (74%) were identified at the community clinic. Of 5863 specimens screened at the community clinic, 105 (1.8%) had EIA-RR/WB-positive/NAAT-positive results, and 26 (0.4%) met the AHI case definition. Adding NAAT to first-generation EIA screening at the community clinic increased HIV case detection by 24.7%. Of the 26 persons with AHI, 12 (46%) were detected with the third-generation assay, decreasing the yield of NAAT to 11.9%.

The other 9 persons with AHI were identified at the Los Angeles STD clinics, where NAAT after first-generation screening increased HIV case detection by 2.8%. Five of the AHI cases were detected with the third-generation assay, decreasing the yield of NAAT to 1.5%.

In New York, from June 1, 2007, through March 28, 2008, 6547 specimens underwent screening for HIV. Of these, 6481 (99.0%) had RT-negative/NAAT-negative findings, and 29 (0.4%) had RT-positive/WB-positive/NAAT-positive findings. Seven individuals (0.1%) had test results that met the AHI case definition. Adding NAAT to second-generation RT screening in New York increased HIV case detection by 24.1%. Of the 7 persons with AHI, the infection was detected in 6 (85.7%) with the third-generation assay, decreasing the yield of NAAT to 2.9% (Table 3).

In Florida, from April 1, 2006, to February 29, 2008, 54 948 specimens underwent screening for HIV. Of these, 54 180 (98.6%) had EIA-negative/NAAT-negative results, and 663 (1.2%) had EIA-RR/WB-positive results. Fifteen individuals had test results that met the AHI case definition, of whom 3 had false-positive NAAT results. Of the 12 persons with AHI, 7 had EIA-negative/NAAT-positive results, 2 had EIA-RR/WB-negative/NAAT-positive results, and 3 had EIA-RR/WB-indeterminate/NAAT-positive results. Adding NAAT to third-generation EIA screening in Florida increased HIV case detection by 1.4% (Table 3).

In Florida, from September 1, 2007, through February 29, 2008, 604 specimens were received from RT sites, of which 586 (97.0%) had negative RT results (OraQuick) and 17 (2.8%) had positive results confirmed by WB. One individual had test results that met the AHI case definition. This AHI case had a negative third-generation test result (Table 3). Adding NAAT to second-generation RT screening in Florida increased HIV case detection by 5.9%.

Of all 99 111 specimens undergoing testing for HIV in all 3 project areas, 97 908 (98.8%) had negative results with the third-generation assay and 1160 (1.2%) had positive results. Twenty-six individuals had NAAT-positive results and were considered AHI cases. Therefore, pooled NAAT after negative third-generation test results increased HIV case detection by 2.2% (range by site: 1.4%-5.9%) (Table 3).

CASE AND PARTNER NOTIFICATION

Of the 55 persons identified with AHI, 48 (87%) received their NAAT result and 7 were lost to follow-up; 12 of the 55 (22%) reported a recent known exposure to HIV. Of the 48 persons who received their results, 11 (23%) received their results within 7 days of testing; 23 (48%), within 8 to 14 days of testing; and 14 (29%), more than 14 days after testing (Table 4). The Florida sites had the longest turnaround time of reporting NAAT results to persons with AHI. We experienced courier-related shipping delays in Los Angeles and Florida that rendered many specimens unsatisfactory for testing. To increase specimen integrity, we switched from EDTA to plasma preparation tubes that required centrifugation. Also, Los Angeles specimens were shipped across the country to New York for NAAT after the Los Angeles public health laboratory performed initial HIV-antibody screening. Therefore, Los Angeles had the longest turnaround time of NAAT results from the laboratory to the health department (Table 4).

Table Graphic Jump LocationTable 4. NAAT Results Reporting and Partner Notification Outcomes, CDC Acute HIV Infection Study by Project Area, 2006-2008

Of the 48 persons with AHI who received their results, all accepted partner notification services. These persons named 72 partners; 23 of these (32%) underwent testing, of whom 5 (21.7%) were found to be HIV-positive. Two partners were pregnant women, both of whom had HIV-negative results.

PERFORMANCE OF POOLED NAAT

Of the 59 persons with presumptive AHI, 48 had documented seroconversion based on follow-up testing, and 7 were lost to follow-up. Four persons with presumptive AHI had negative NAAT results and an undetectable viral load on follow-up testing and were classified as false-positive cases. The distribution of the initial test results of the 4 false-positive cases included 1 EIA-negative/NAAT-positive result, 2 EIA-RR/WB-negative/NAAT-positive results, and 1 EIA-RR/WB-indeterminate/NAAT-positive result. All 55 persons with AHI had a detectable viral load (median, 310 975 [range, 92-6 334 400] copies/mL). Overall, the positive predictive value of pooled NAAT for identifying AHI among antibody-negative specimens was 0.9804 (95% confidence interval [CI], 0.9071-0.9990) with a specificity of 0.9998 (95% CI, 0.9992-1.000). Sensitivity cannot be estimated because the NAAT-negative pools were not deconstructed and confirmed negative. Forty-two persons with EIA-RR/WB-positive results had NAAT-negative results (Table 3); 28 of these persons (67%) were known to be seropositive, with a history of antiretroviral use.

PERFORMANCE OF FOURTH-GENERATION TESTING

Of the 55 persons with AHI, 27 had enough plasma for fourth-generation testing, and 23 of these (85%) had positive findings. The fourth-generation assay detected 10 of 13 AHI cases (77%) that were missed by the third-generation assay. The 4 AHI specimens with negative fourth-generation assay results also had negative third-generation assay results. These 4 cases had a median viral load of 6961 (range, 1827-21 548) copies/mL. Pooled NAAT after negative fourth-generation testing may have increased HIV case detection by only 0.7%. Furthermore, fourth-generation testing of the blinded specimen panel resulted in 2 false-positive and 4 false-negative results. Therefore, the sensitivity of the Architect HIV Ag/Ab Combo assay compared with NAAT was 0.9506 (95% CI, 0.8852-0.9841), and specificity was 0.9834 (95% CI, 0.9456-0.9972).

This is, to our knowledge, the first study to compare the yield of NAAT after screening with different antibody tests. Our data suggest that pooled NAAT increases HIV case detection most when used with less sensitive screening immunoassays.3136 However, the third-generation EIA was able to detect HIV infection in 50.9% of all AHI cases identified in this study. Thus, pooled NAAT after screening with a third-generation EIA increased our HIV case detection by 2.2% overall. The marginal yield of pooled NAAT after third-generation testing, however, may be even more substantial in targeted screening of high-risk persons. In Los Angeles, pooled NAAT after third-generation testing resulted in the highest increase in HIV case detection at the community center (11.9%), where HIV positivity was the highest. This suggests that targeted AHI screening at high-risk/high-incidence venues using pooled NAAT may be most effective.

According to the Association of Public Health Laboratories survey,45 of all laboratories surveyed in 2006, most (58%) were using a first-generation assay that is no longer available today. Given our study results, public health laboratories should consider using the most sensitive EIA available for HIV screening, which currently is a third-generation assay, in the absence of NAAT for antibody-negative specimens. Although only half of the AHI cases underwent retrospective fourth-generation testing, 85.1% of those tested were detected. These data suggest that pooled NAAT after negative fourth-generation testing may increase HIV case detection by only 0.7%. Although fourth-generation assays are the preferred test for HIV screening among routine testing populations in other countries, none are available for use in the United States. The marginal yield (0.7%) of NAAT after fourth-generation testing in our study was similar to findings (1.1%) reported in Australia.37 The AHI cases missed by fourth-generation testing had low viral loads, suggesting early acute-phase infection. Hence, the yield of pooled NAAT after fourth-generation testing may be maximized in high-incidence populations where early AHI cases are most probable. Further evaluation of NAAT after fourth-generation testing in high-risk/high-incidence settings is warranted.

Detection of AHI can only realize its full HIV prevention potential with timely reporting of results and partner notification. In our study, 48 AHI cases (87%) received their results and accepted partner notification services; only 11 (23%) received their results within 7 days and only 23 of the named partners (32%) underwent testing. To interrupt further transmission, persons with AHI should be located immediately, preferably within 72 hours of testing, and their sexual contacts should be urgently located and undergo testing.46,47 Studies have shown that partners of HIV-positive persons who accept partner notification services have rates of HIV positivity as high as 57%.4850 However, many local health departments, including our study sites, have limited capacity and insufficient funding for their partner notification programs and are therefore able to locate only a small number of partners in a timely manner. To maximize HIV screening services (with or without NAAT), partner notification programs should be strengthened so that they have a better capacity to find at-risk partners and use novel and innovative strategies5153 to locate and test persons quickly to preclude further HIV transmission.

Our study had several limitations. First, we implemented the study differently in each project area to accommodate existing program procedures, which limited our ability to compare all outcomes across project areas. Specifically, New York implemented a separate consent for NAAT, which led to client self-selection for NAAT. As a result, our findings might overestimate the yield of NAAT in New York if clients were more likely to opt for AHI screening because of recent high-risk behaviors. Second, shipping delays increased the turnaround time for reporting results in Los Angeles. Third, we did not conduct a real-time evaluation of fourth-generation assays because they are not currently available in the United States, and we tested a small subset of specimens, which may have introduced a potential bias. Finally, NAAT may miss persons with long-standing HIV infection; we had 42 false-negative NAAT results (Figure 2). Moreover, there is an eclipse phase of 10 to 11 days after initial HIV infection during which HIV viremia is undetectable.27 Given that the length of the eclipse phase is similar to the window period with third-generation assays, the number of infections missed by NAAT during this phase may be equal to the number of AHIs detected among seronegative persons. Thus, particularly in high-incidence sites like the Los Angeles community clinic, patients should be encouraged to undergo retesting, especially after a risk exposure, consistent with current CDC recommendations.44

Adding NAAT to HIV screening programs adds cost because pooled NAAT is feasible only after antibody testing (both must be performed). However, the cost of NAAT reported from previous studies has varied with the number of persons with AHIs identified.30,31,33 Furthermore, although NAAT is more expensive than immunoassays, the fourth-generation immunoassay cannot distinguish between acute and prevalent HIV infection; this would require supplemental testing, adding to cost. Therefore, formal cost and cost-effectiveness analyses are under way.

Screening for AHI can maximize HIV case detection. However, implementing strategies to distinguish AHI from prevalent HIV infection maximizes prevention benefits only if programs are able to (1) provide referral for appropriate clinical management, (2) conduct urgent partner notification and testing, and (3) investigate foci or networks of HIV transmission. Our study supports AHI screening with pooled NAAT after third-generation assays in areas of high HIV prevalence. Therefore, targeted AHI screening using pooled NAAT after third-generation testing may be most effective. Further studies of AHI screening with new testing technologies among high-risk/high-incidence populations are warranted. Finally, when fourth-generation assays become available in the United States, it is less clear whether NAAT should play a role in AHI screening programs.

Correspondence: Pragna Patel, MD, MPH, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, 1600 Clifton Rd, Mail Stop E-45, Atlanta, GA 30333 (plp3@cdc.gov).

Accepted for Publication: September 11, 2009.

Author Contributions:Study concept and design: Patel, Mackellar, Bennett, Kerndt, and P. S. Sullivan. Acquisition of data: Patel, Mackellar, Simmons, Uniyal, Gallagher, Bennett, T. J. Sullivan, Kowalski, Parker, LaLota, and Kerndt. Analysis and interpretation of data: Patel, Gallagher, Bennett, Kerndt, and P. S. Sullivan. Drafting of the manuscript: Patel. Critical revision of the manuscript for important intellectual content: Patel, Mackellar, Simmons, Uniyal, Gallagher, Bennett, T. J. Sullivan, Kowalski, Parker, LaLota, Kerndt, and P. S. Sullivan. Statistical analysis: Patel. Obtained funding: Uniyal, Kerndt, and P. S. Sullivan. Administrative, technical, and material support: Patel, Mackellar, Simmons, Gallagher, Bennett, T. J. Sullivan, Kowalski, Parker, Kerndt, and P. S. Sullivan. Study supervision: Patel, Mackellar, Bennett, Kerndt, and P. S. Sullivan.

CDC Acute HIV Infection Study Group: In addition to the authors of this article, the group includes: Michael Chien, MPH, Staeci Morita, BS, La Shawnda Royal, and Ali Stirland, MBChB, MSc, from the Los Angeles Department of Health Services; Melinda Waters, BS, from the Florida Department of Health; Sally Fordan, BS, Olanike David, MS, and Petrice Stephens, BS, from the Florida Bureau of Laboratories; Kathy Gombel, BS, and Judith Wethers, MS, from the Wadsworth Center, New York State Department of Health; Susan Blank, MD, MPH, and Steve Rubin, BA, from the New York City Department of Health and Mental Hygiene; and Steven Ethridge, MT, and Huisheng Wang, MD, from the CDC.

Financial Disclosure: Dr Kerndt was a consultant to GenProbe Inc in 2005, before APTIMA HIV-1 RNA was approved by the US Food and Drug Administration or considered for this study.

Funding/Support: This study was supported by grant 1 UA1 PS000063 from the CDC.

Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the CDC.

Additional Contributions: Sheryl Lyss, MD, MPH, contributed to the concept of this study, and Bernard Branson, MD, contributed to the study concept and provided thoughtful review of this manuscript.

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Yerly  SVora  SRizzardi  P  et al. Swiss HIV Cohort Study, Acute HIV infection: impact on the spread of HIV and transmission of drug resistance. AIDS 2001;15 (17) 2287- 2292
PubMed Link to Article
Pao  DFisher  MHué  S  et al.  Transmission of HIV-1 during primary infection: relationship to sexual risk and sexually transmitted infections. AIDS 2005;19 (1) 85- 90
PubMed Link to Article
Hightow-Weidman  LBGolin  CEGreen  KShaw  ENPMacDonald  PDMLeone  PA Identifying people with acute HIV infection: demographic features, risk factors, and use of health care among individuals with AHI in North Carolina [published online January 6, 2009]. AIDS Behav 2009;
PubMed
PubMed
Leynaert  BDowns  AMde Vincenzi  IEuropean Study Group on Heterosexual Transmission of HIV, Heterosexual transmission of human immunodeficiency virus: variability of infectivity throughout the course of infection. Am J Epidemiol 1998;148 (1) 88- 96
PubMed Link to Article
Royce  RASena  SCates  W  JrCohen  MS Sexual transmission of HIV. N Engl J Med 1997;336 (15) 1072- 1078
PubMed Link to Article
Hollingsworth  TDAnderson  RMFraser  C HIV-1 transmission, by stage of infection. J Infect Dis 2008;198 (5) 687- 693
PubMed Link to Article
Wawer  MJGray  RHSewankambo  NK  et al.  Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis 2005;191 (9) 1403- 1409
PubMed Link to Article
Brenner  BGRoger  MRouty  JP  et al. Quebec Primary HIV Infection Study Group, High rates of forward transmission events after acute/early HIV-1 infection. J Infect Dis 2007;195 (7) 951- 959
PubMed Link to Article
Lewis  FHughes  GJRambaut  APozniak  ALeigh Brown  AJ Episodic sexual transmission of HIV revealed by molecular phylodynamics. PLoS Med 2008;5 (3) e50
PubMed
PubMed Link to Article
Pinkerton  SD How many sexually-acquired HIV infections in the USA are due to acute-phase HIV transmission? AIDS 2007;21 (12) 1625- 1629
PubMed Link to Article
Rapatski  BLSuppe  FYorke  JA HIV epidemics driven by late disease stage transmission. J Acquir Immune Defic Syndr 2005;38 (3) 241- 253
PubMed
Kilmarx  PHHamers  FFPeterman  TA Living with HIV: experiences and perspectives of HIV-infected sexually transmitted disease clinic patients after posttest counseling. Sex Transm Dis 1998;25 (1) 28- 37
PubMed Link to Article
Weinhardt  LSCarey  MPJohnson  BTBickham  NL Effects of HIV counseling and testing on sexual risk behavior: a meta-analytic review of published research, 1985-1997. Am J Public Health 1999;89 (9) 1397- 1405
PubMed Link to Article
Colfax  GNBuchbinder  SPCornelisse  PGAVittinghoff  EMayer  KCelum  C Sexual risk behaviors and implications for secondary HIV transmission during and after HIV seroconversion. AIDS 2002;16 (11) 1529- 1535
PubMed Link to Article
Marks  GCrepaz  NSenterfitt  WJanssen  RS Meta-analysis of high-risk sexual behavior in persons aware and unaware they are infected with HIV in the United States: implications for HIV prevention programs. J Acquir Immune Defic Syndr 2005;39 (4) 446- 453
PubMed Link to Article
Constantine  NTSaville  RDDax  EM Retroviral Testing and Quality Assurance: Essentials for Laboratory Diagnosis.  Halifax, Nova Scotia: MedMira Laboratories; 2005:147-151
Fiebig  EWWright  DJRawal  BD  et al.  Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS 2003;17 (13) 1871- 1879
PubMed Link to Article
Busch  MPLee  LLJSatten  GA  et al.  Time course of detection of viral and serologic markers preceding human immunodeficiency virus type 1 seroconversion: implications for screening of blood and tissue donors. Transfusion 1995;35 (2) 91- 97
PubMed Link to Article
Stramer  SLGlynn  SAKleinman  SH  et al. National Heart, Lung, and Blood Institute Nucleic Acid Test Study Group, Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. N Engl J Med 2004;351 (8) 760- 768
PubMed Link to Article
Pilcher  CD McPherson  JTLeone  PA  et al.  Real-time, universal screening for acute HIV infection in a routine HIV counseling and testing population. JAMA 2002;288 (2) 216- 221
PubMed Link to Article
Pilcher  CDFiscus  SANguyen  TQ  et al.  Detection of acute infections during HIV testing in North Carolina. N Engl J Med 2005;352 (18) 1873- 1883
PubMed Link to Article
Stekler  JSwenson  PDWood  RWHandsfield  HHGolden  MR Targeted screening for primary HIV infection through pooled HIV-RNA testing in men who have sex with men. AIDS 2005;19 (12) 1323- 1325
PubMed Link to Article
Patel  PKlausner  JDBacon  OM  et al.  Detection of acute HIV infections in high-risk patients in California. J Acquir Immune Defic Syndr 2006;42 (1) 75- 79
PubMed Link to Article
Truong  HMGrant  RM McFarland  W  et al.  Routine surveillance for the detection of acute and recent HIV infections and transmission of antiretroviral resistance. AIDS 2006;20 (17) 2193- 2197
PubMed Link to Article
Priddy  FHPilcher  CDMoore  RH  et al.  Detection of acute HIV infections in an urban HIV counseling and testing population in the United States. J Acquir Immune Defic Syndr 2007;44 (2) 196- 202
PubMed Link to Article
Hecht  FMBusch  MPRawal  B  et al.  Use of laboratory test and clinical symptoms for identification of primary HIV infection. AIDS 2002;16 (8) 1119- 1129
PubMed Link to Article
Cunningham  PH McNally  LPFinlayson  R  et al Enhanced surveillance of acute HIV-1 infection in inner Sydney [abstract WEPDC04].  Poster presented at: Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia
Louie  BWong  EKlausner  JD  et al.  Assessment of rapid tests for detection of human immunodeficiency virus-specific antibodies in recently infected individuals. J Clin Microbiol 2008;46 (4) 1494- 1497
PubMed Link to Article
 Aptima HIV-1 RNA Qualitative Assay [package insert].  San Diego, CA: GenProbe Inc; August2008
Ethridge  SSullivan  TBennett  B  et al Validating 16 member pooled APTIMA® HIV-1 RNA testing [abstract 55].  Paper presented at: 2007 HIV Diagnostics Conference; December 5, 2007; Atlanta, Georgia
Fleiss  JL Statistical Methods for Rates and Proportions. 2nd ed. New York, NY: John Wiley & Sons; 1981
Rosner  B Fundamentals of Biostatistics. 5th ed. Duxbury, MA: Duxbury Press; 2000
Rothman  KJBoice  JD  Jr Epidemiologic Analysis With a Programmable Calculator.  Bethesda, MD: National Institutes of Health; 1979:31-32. NIH publication 79-1649
Centers for Disease Control and Prevention, Revised guidelines for HIV counseling, testing, and referral and revised recommendation of HIV screening of pregnant women. MMWR Recomm Rep 2001;50 (RR-19) 1- 54
PubMed
Association of Public Health Laboratories Public health laboratory issues in brief: 2006 HIV diagnostics survey. http://www.aphl.org/aphlprograms/infectious/Documents/HIV_issue_brief_2007.pdf. Accessed October 16, 2008
Centers for Disease Control and Prevention (CDC), Recommendations for partner services program for HIV infection, syphilis, gonorrhea, and chlamydial infection. MMWR Recomm Rep 2008;57 (RR-9) 1- 83
PubMed
Marcus  JLBernstein  KTKlausner  JD Updated outcomes of partner notification for human immunodeficiency virus, San Francisco, 2004-2008 [published online April 1, 2009]. AIDS 2009;23 (8) 1024- 1026
PubMed
PubMed Link to Article
Hogben  M McNally  T McPheeters  MHutchinson  AB The effectiveness of HIV partner counseling and referral services in increasing identification of HIV-positive individuals: a systematic review. Am J Prev Med 2007;33 (2) (suppl)S89- S100
PubMed Link to Article
Golden  MRHogben  MPotterat  JJHandsfield  HH HIV partner notification in the United States: a national survey of program coverage and outcomes. Sex Transm Dis 2004;31 (12) 709- 712
PubMed Link to Article
Brewer  DD Case-finding effectiveness of partner notification and cluster investigation for sexually transmitted diseases/HIV. Sex Transm Dis 2005;32 (2) 78- 83
PubMed Link to Article
Klausner  JDWolf  WFischer-Ponce  LZolt  IKatz  MH Tracing a syphilis outbreak through cyberspace. JAMA 2000;284 (4) 447- 449
PubMed Link to Article
Centers for Disease Control and Prevention, Using the Internet for partner notification of sexually transmitted diseases: Los Angeles County, California, 2003. MMWR Morb Mortal Wkly Rep 2004;53 (6) 129- 131
PubMed
Hogben  MKachur  R Internet partner notification: another arrow in the quiver. Sex Transm Dis 2008;35 (2) 117- 118
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Window of detection of human immunodeficiency virus (HIV) markers early in HIV infection and window period of different enzyme immunoassays compared with nucleic acid amplification testing (NAAT) for HIV RNA. EIA indicates enzyme immunoassay. Data from Fiebig et al27; the figure was adapted from a graphic courtesy of Steven Kleinman, MD.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Human immunodeficiency virus (HIV) screening algorithm with pooled nucleic acid amplification testing (NAAT) for the Centers for Disease Control and Prevention Acute HIV Infection Study, 2006-2008. EIA indicates enzyme immunoassay. The proprietary information on the EIAs and APTIMA HIV-1 Assay is given in the “Testing Protocol” subsection of the “Methods” section. *Positive pools and individual specimens underwent testing in duplicate for suspected acute/primary HIV infection.39 †Persons with specimens with positive NAAT results but an undetectable viral load underwent follow-up testing to resolve discrepant results.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Summary of Studies That Have Reported Acute HIV Case Detection Using Pooled NAAT in the United States
Table Graphic Jump LocationTable 2. Characteristics of CDC Acute HIV Infection Study Population and Project Areas, 2006-2008a
Table Graphic Jump LocationTable 3. CDC Acute HIV Infection Study Results by Project Area, 2006-2008a
Table Graphic Jump LocationTable 4. NAAT Results Reporting and Partner Notification Outcomes, CDC Acute HIV Infection Study by Project Area, 2006-2008

References

Quinn  TC Acute primary HIV infection. JAMA 1997;278 (1) 58- 62
PubMed Link to Article
Daar  ESMoudgil  TMeyer  RDHo  DD Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N Engl J Med 1991;324 (14) 961- 964
PubMed Link to Article
Clark  SJSaag  MSDecker  WD  et al.  High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. N Engl J Med 1991;324 (14) 954- 960
PubMed Link to Article
Tindall  BEvans  LCunningham  P  et al.  Identification of HIV-1 in semen following primary HIV-1 infection. AIDS 1992;6 (9) 949- 952
PubMed Link to Article
Pilcher  CDShugars  DCFiscus  SA  et al.  HIV in body fluids during primary HIV infection: implications for pathogenesis, treatment, and public health. AIDS 2001;15 (7) 837- 845
PubMed Link to Article
Quinn  TCWawer  MJSewankambo  N  et al. Rakai Project Study Group, Viral load and heterosexual transmission of human immunodeficiency virus type 1. N Engl J Med 2000;342 (13) 921- 929
PubMed Link to Article
Koopman  JSJacquez  JAWelch  GW  et al.  The role of early HIV infection in the spread of HIV through populations. J Acquir Immune Defic Syndr Hum Retrovirol 1997;14 (3) 249- 258
PubMed Link to Article
Jacquez  JAKoopman  JSSimon  CPLongini  IM  Jr Role of the primary infection in epidemics of HIV infection in gay cohorts. J Acquir Immune Defic Syndr 1994;7 (11) 1169- 1184
PubMed
Pilcher  CDTien  HCEron  JJ  Jr  et al. Quest Study; Duke-UNC-Emory Acute HIV Consortium, Brief but efficient: acute HIV infection and the sexual transmission of HIV. J Infect Dis 2004;189 (10) 1785- 1792
PubMed Link to Article
Pilcher  CDEron  JJ  JrVemazza  PL  et al.  Sexual transmission during the incubation period of primary HIV infection. JAMA 2001;286 (14) 1713- 1714
PubMed Link to Article
Yerly  SVora  SRizzardi  P  et al. Swiss HIV Cohort Study, Acute HIV infection: impact on the spread of HIV and transmission of drug resistance. AIDS 2001;15 (17) 2287- 2292
PubMed Link to Article
Pao  DFisher  MHué  S  et al.  Transmission of HIV-1 during primary infection: relationship to sexual risk and sexually transmitted infections. AIDS 2005;19 (1) 85- 90
PubMed Link to Article
Hightow-Weidman  LBGolin  CEGreen  KShaw  ENPMacDonald  PDMLeone  PA Identifying people with acute HIV infection: demographic features, risk factors, and use of health care among individuals with AHI in North Carolina [published online January 6, 2009]. AIDS Behav 2009;
PubMed
PubMed
Leynaert  BDowns  AMde Vincenzi  IEuropean Study Group on Heterosexual Transmission of HIV, Heterosexual transmission of human immunodeficiency virus: variability of infectivity throughout the course of infection. Am J Epidemiol 1998;148 (1) 88- 96
PubMed Link to Article
Royce  RASena  SCates  W  JrCohen  MS Sexual transmission of HIV. N Engl J Med 1997;336 (15) 1072- 1078
PubMed Link to Article
Hollingsworth  TDAnderson  RMFraser  C HIV-1 transmission, by stage of infection. J Infect Dis 2008;198 (5) 687- 693
PubMed Link to Article
Wawer  MJGray  RHSewankambo  NK  et al.  Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis 2005;191 (9) 1403- 1409
PubMed Link to Article
Brenner  BGRoger  MRouty  JP  et al. Quebec Primary HIV Infection Study Group, High rates of forward transmission events after acute/early HIV-1 infection. J Infect Dis 2007;195 (7) 951- 959
PubMed Link to Article
Lewis  FHughes  GJRambaut  APozniak  ALeigh Brown  AJ Episodic sexual transmission of HIV revealed by molecular phylodynamics. PLoS Med 2008;5 (3) e50
PubMed
PubMed Link to Article
Pinkerton  SD How many sexually-acquired HIV infections in the USA are due to acute-phase HIV transmission? AIDS 2007;21 (12) 1625- 1629
PubMed Link to Article
Rapatski  BLSuppe  FYorke  JA HIV epidemics driven by late disease stage transmission. J Acquir Immune Defic Syndr 2005;38 (3) 241- 253
PubMed
Kilmarx  PHHamers  FFPeterman  TA Living with HIV: experiences and perspectives of HIV-infected sexually transmitted disease clinic patients after posttest counseling. Sex Transm Dis 1998;25 (1) 28- 37
PubMed Link to Article
Weinhardt  LSCarey  MPJohnson  BTBickham  NL Effects of HIV counseling and testing on sexual risk behavior: a meta-analytic review of published research, 1985-1997. Am J Public Health 1999;89 (9) 1397- 1405
PubMed Link to Article
Colfax  GNBuchbinder  SPCornelisse  PGAVittinghoff  EMayer  KCelum  C Sexual risk behaviors and implications for secondary HIV transmission during and after HIV seroconversion. AIDS 2002;16 (11) 1529- 1535
PubMed Link to Article
Marks  GCrepaz  NSenterfitt  WJanssen  RS Meta-analysis of high-risk sexual behavior in persons aware and unaware they are infected with HIV in the United States: implications for HIV prevention programs. J Acquir Immune Defic Syndr 2005;39 (4) 446- 453
PubMed Link to Article
Constantine  NTSaville  RDDax  EM Retroviral Testing and Quality Assurance: Essentials for Laboratory Diagnosis.  Halifax, Nova Scotia: MedMira Laboratories; 2005:147-151
Fiebig  EWWright  DJRawal  BD  et al.  Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS 2003;17 (13) 1871- 1879
PubMed Link to Article
Busch  MPLee  LLJSatten  GA  et al.  Time course of detection of viral and serologic markers preceding human immunodeficiency virus type 1 seroconversion: implications for screening of blood and tissue donors. Transfusion 1995;35 (2) 91- 97
PubMed Link to Article
Stramer  SLGlynn  SAKleinman  SH  et al. National Heart, Lung, and Blood Institute Nucleic Acid Test Study Group, Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. N Engl J Med 2004;351 (8) 760- 768
PubMed Link to Article
Pilcher  CD McPherson  JTLeone  PA  et al.  Real-time, universal screening for acute HIV infection in a routine HIV counseling and testing population. JAMA 2002;288 (2) 216- 221
PubMed Link to Article
Pilcher  CDFiscus  SANguyen  TQ  et al.  Detection of acute infections during HIV testing in North Carolina. N Engl J Med 2005;352 (18) 1873- 1883
PubMed Link to Article
Stekler  JSwenson  PDWood  RWHandsfield  HHGolden  MR Targeted screening for primary HIV infection through pooled HIV-RNA testing in men who have sex with men. AIDS 2005;19 (12) 1323- 1325
PubMed Link to Article
Patel  PKlausner  JDBacon  OM  et al.  Detection of acute HIV infections in high-risk patients in California. J Acquir Immune Defic Syndr 2006;42 (1) 75- 79
PubMed Link to Article
Truong  HMGrant  RM McFarland  W  et al.  Routine surveillance for the detection of acute and recent HIV infections and transmission of antiretroviral resistance. AIDS 2006;20 (17) 2193- 2197
PubMed Link to Article
Priddy  FHPilcher  CDMoore  RH  et al.  Detection of acute HIV infections in an urban HIV counseling and testing population in the United States. J Acquir Immune Defic Syndr 2007;44 (2) 196- 202
PubMed Link to Article
Hecht  FMBusch  MPRawal  B  et al.  Use of laboratory test and clinical symptoms for identification of primary HIV infection. AIDS 2002;16 (8) 1119- 1129
PubMed Link to Article
Cunningham  PH McNally  LPFinlayson  R  et al Enhanced surveillance of acute HIV-1 infection in inner Sydney [abstract WEPDC04].  Poster presented at: Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia
Louie  BWong  EKlausner  JD  et al.  Assessment of rapid tests for detection of human immunodeficiency virus-specific antibodies in recently infected individuals. J Clin Microbiol 2008;46 (4) 1494- 1497
PubMed Link to Article
 Aptima HIV-1 RNA Qualitative Assay [package insert].  San Diego, CA: GenProbe Inc; August2008
Ethridge  SSullivan  TBennett  B  et al Validating 16 member pooled APTIMA® HIV-1 RNA testing [abstract 55].  Paper presented at: 2007 HIV Diagnostics Conference; December 5, 2007; Atlanta, Georgia
Fleiss  JL Statistical Methods for Rates and Proportions. 2nd ed. New York, NY: John Wiley & Sons; 1981
Rosner  B Fundamentals of Biostatistics. 5th ed. Duxbury, MA: Duxbury Press; 2000
Rothman  KJBoice  JD  Jr Epidemiologic Analysis With a Programmable Calculator.  Bethesda, MD: National Institutes of Health; 1979:31-32. NIH publication 79-1649
Centers for Disease Control and Prevention, Revised guidelines for HIV counseling, testing, and referral and revised recommendation of HIV screening of pregnant women. MMWR Recomm Rep 2001;50 (RR-19) 1- 54
PubMed
Association of Public Health Laboratories Public health laboratory issues in brief: 2006 HIV diagnostics survey. http://www.aphl.org/aphlprograms/infectious/Documents/HIV_issue_brief_2007.pdf. Accessed October 16, 2008
Centers for Disease Control and Prevention (CDC), Recommendations for partner services program for HIV infection, syphilis, gonorrhea, and chlamydial infection. MMWR Recomm Rep 2008;57 (RR-9) 1- 83
PubMed
Marcus  JLBernstein  KTKlausner  JD Updated outcomes of partner notification for human immunodeficiency virus, San Francisco, 2004-2008 [published online April 1, 2009]. AIDS 2009;23 (8) 1024- 1026
PubMed
PubMed Link to Article
Hogben  M McNally  T McPheeters  MHutchinson  AB The effectiveness of HIV partner counseling and referral services in increasing identification of HIV-positive individuals: a systematic review. Am J Prev Med 2007;33 (2) (suppl)S89- S100
PubMed Link to Article
Golden  MRHogben  MPotterat  JJHandsfield  HH HIV partner notification in the United States: a national survey of program coverage and outcomes. Sex Transm Dis 2004;31 (12) 709- 712
PubMed Link to Article
Brewer  DD Case-finding effectiveness of partner notification and cluster investigation for sexually transmitted diseases/HIV. Sex Transm Dis 2005;32 (2) 78- 83
PubMed Link to Article
Klausner  JDWolf  WFischer-Ponce  LZolt  IKatz  MH Tracing a syphilis outbreak through cyberspace. JAMA 2000;284 (4) 447- 449
PubMed Link to Article
Centers for Disease Control and Prevention, Using the Internet for partner notification of sexually transmitted diseases: Los Angeles County, California, 2003. MMWR Morb Mortal Wkly Rep 2004;53 (6) 129- 131
PubMed
Hogben  MKachur  R Internet partner notification: another arrow in the quiver. Sex Transm Dis 2008;35 (2) 117- 118
PubMed Link to Article

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