The fourth generation Alere™ HIV Combo rapid test improves detection of acute infection in MTN-003 (VOICE) samples

Background: Early and accurate detection of HIV is crucial when using pre-exposure prophylaxis (PrEP) for HIV prevention to avoid PrEP initiation in acutely infected individuals and to minimize the risk of drug resistance in individuals with breakthrough infection. Objective: To determine if fourth-generation antigen/antibody (Ag/Ab) rapid diagnostic tests (RDT) would have detected HIV infection earlier than the third-generation RDT used in MTN-003 (VOICE). Study design: 5029 VOICE participants were evaluated with third-generation Alere Determine (TM) HIV-1/2, OraQuick ADVANCE (R) Rapid HIV-1/2, Uni-Gold (TM) Recombigen (R) HIV-1/2 and Bio-Rad GS HIV-1/2+ O EIA; and fourth-generation Alere Determine (TM) HIV-1/2 Ag/Ab Combo, Conformite Europeene (CE)-Marked Alere (TM) HIV Combo and Bio-Rad HIV Combo Ag/Ab EIA. Multispot (R), GS HIV-1 Western Blot (WB) and Geenius (TM) (Bio-Rad) were also evaluated. Results: Of 57 antibody-negative pre-seroconversion plasma samples with HIV RNA > 20 copies/mL identified, 16 (28%) were reactive by CE-Marked Alere (TM) HIV Combo (1 Ab; 9 Ag; 6 Ag/Ab reactive) and 4 (7%) by Alere Determine (TM) HIV-1/2 Ag/Ab Combo (2 Ab; 2 Ag; 0 Ag/Ab reactive) (p = 0.0005). Multispot (R) confirmed only 1 of 16 acute infections while WB and Geenius (TM) confirmed none. GS HIV Combo Ag/Ab EIA identified 27 of 57 (47%) pre-seroconversion RNA-positive samples. Conclusion: In VOICE, 28% of infections missed by current third-generation RDT would have been identified with the use of CE-Marked Alere (TM) HIV Combo. Geenius (TM), Multispot (R) and WB were all insensitive (< 10%) in confirming infections detected by fourth-generation assays. An improved diagnostic algorithm that includes a fourth-generation RDT with HIV RNA testing will be essential for efficiently identifying seroconverters on PrEP.