Poor Performance of the Determine HIV-1/2 Ag/Ab Combo ...

1 Poor Performance of the Determine HIV-1/2 Ag/Ab Combo Fourth-Generation Rapid Test for Detection of Acute Infections in a NationalHousehold Survey in SwazilandYen T. Duong,aYvonne Mavengere,bHetal Patel,aCarole Moore,aJulius Manjengwa,bDumile Sibandze,dChristopher Rasberry,aCharmaine Mlambo,bZhi Li,cLynda Emel,cNaomi Bock,aJan Moore,aRejoice Nkambule,dJessica Justman,bJason Reed,aGeorge Bicego,eDennis L. Ellenberger,aJohn N. Nkengasong,aBharat S. ParekhaDivision of Global HIV/AIDS, Centers for Disease Control and Prevention, Atlanta, Georgia, USAa; ICAP, Mailman School of Public Health, Columbia University, New York,New York, USAb; Statistical Center for HIV/AIDS Research and Prevention (SCHARP), Fred Hutchison Cancer Research Center, Seattle, Washington, USAc; Ministry of Health,Mbabane, Swazilandd.

2 Centers for Disease Control and Prevention, Mbabane, SwazilandeFourth-generation HIV rapid tests (RTs) claim to detect both p24 antigen (Ag) and HIV antibodies (Ab) for early identificationof acute infections, important for targeting prevention and reducing HIV transmission. In a nationally representative householdsurvey in swaziland , 18,172 adults, age 18 to 49 years, received home-based HIV rapid testing in 2010 and 2011. Of the 18,172individuals, 5,822 ( ) were Ab positive (Ab ) by the Determine HIV-1/2 Ab/Ab Combo test, and 5,789 ( ) of those wereconfirmed to be reactive in the Uni-Gold test.

3 Determine Combo identified 12 individuals as having acute infections (Ag /Abnegative [Ab ]); however, none had detectable HIV-1 RNA and 8 of 12 remained HIV negative at their 6-week follow-up visit (4were lost to follow-up). All RT-nonreactive samples were pooled and tested by nucleic acid amplification testing (NAAT) to iden-tify acute infections. NAAT identified 13 ( ) of the 12,338 HIV antibody-negative specimens as HIV RNA positive, with RNAlevels ranging from 300 to>10,000,000 copies/ml. However, none of them were Ag by Determine Combo .

4 Follow-up testing of12 of the 13 NAAT-positive individuals at 6 months demonstrated 12 seroconversions (1 individual was lost to follow-up).Therefore, the Determine Combo test had a sensitivity of 0% (95% confidence interval, 0 to 28) and positive predictive value of0% for the detection of acute infections. The ability of the 4th-generation Determine Combo to detect antigen was very poor inSwaziland. Thus, the Determine Combo test does not add any value to the current testing algorithm; rather, it adds additionalcosts and complexity to HIV diagnosis.

5 The detection of acute HIV infections may need to rely on other testing development of HIV rapid tests (RTs) has facilitated themassive scale-up of HIV testing and counseling at thousandsof testing venues, especially in sub-Saharan Africa, allowing mil-lions of individuals to receive their HIV diagnosis outside a pri-mary care facility (1). HIV RTs have relied on the detection of HIVantibodies(Ab) after seroconversion, and the sensitivities of var-ious RTs have approached nearly 100% (2,3). However, most RTsareunable to detect the acute phase of infection, during whichHIV Ab are absent and only viral nucleic acid or p24 antigen (Ag)may be detectable.

6 Identification of individuals in the acute phaseis considered important in curbing new infections, since the acutephase is characterized by a high viral load, a founder virus capableof efficient infection, and the absence of HIV antibodies, resultingin a greater risk of transmission compared to the risk later ininfection (4 6). Individuals in the acute phase of infection areconsidereddrivers of HIV transmission, accounting for 10 to 50%of new HIV infections (7 9). Thus, it has been suggested thatwhenthese individuals are identified and paired with risk reduc-tion behavioral counseling, treatment, and other intervention andprevention strategies, a major gain in public health by reduction ofthe overall hiv incidence can result (10,11).

7 Thecurrent methods for detection of acute infection are labo-ratory based and require the detection of viral RNA or p24 antigenusing complex, laboratory-based methods. The standard ap-proach for nucleic acid amplification testing (NAAT) employsPCR to detect viral RNA in either individual or pooled HIV-sero-negative samples (12 15), while the occurrence of p24 Ag duringtheacute phase is detected by enzyme-linked immunosorbent as-says (ELISAs), a less commonly used method. Although the sen-sitivity of detection of acute infection by NAAT is high, it requiresscreening a large number of HIV-seronegative individuals due tothe short acute-infection window (approximately 3 to 4 weeks [5,11]).

8 Moreover, such screening is costly, labor-intensive, time-consuming,and thus far, impractical to implement on a largescale. ELISAs that detect only p24 Ag have also had limited use,especially in the United States, where there is no FDA-approvedtest for p24 Ag only. However, 4th-generation HIV diagnosticELISAs have incorporated p24 antigen detection, resulting in si-multaneous detection of both p24 Ag and viral antibodies (16 18). Fourth-generation assays can detect acute infections and havebeenshown to perform well in clinical settings (17); however,additionaltesting of reactive specimens is required to distinguishspecimens that are positive only for antigen.

9 Moreover, theseELISAs require a venous blood draw, a laboratory setting, andskilled laboratory technicians, and there are issues related to turn-Received12 July 2014 Returned for modification29 July 2014 Accepted5 August 2014 Published ahead of print13 August 2014 Editor:A. M. CaliendoAddress correspondence to Bharat S. Parekh, 2014, American Society for Microbiology. All Rights 2014 Volume 52 Number 10 Journal of Clinical Microbiology p. 3743 on February 20, 2019 by from around times and patient follow-up limiting their practical use forthe detection of acute address these issues, p24 Ag detection has recently beenincorporated into a rapid test format to detect both p24 Ag andHIV antibodies as distinct lines and thereby, theoretically, shortenthe diagnostic window period.

10 A rapid test capable of detectingacute infections as well as seropositive infections would allow in-dividuals to know of their infection earlier and in real time (11).Additionally,an Ag/Ab rapid test can be performed by nonlabo-ratorians in testing and counseling facilities where HIV testingcurrently occurs. The Determine HIV-1/2 Ag/Ab Combo rapid testis the first such test that detects both Ag and Ab in two separateindicator lines. Early data on the Performance of the Determinecombo test to detect acute HIV infections in seroconversion pan-els suggested that it had a good Performance in detecting earlyinfections (19,20).