Abstract

Background: Almost all human immunodeficiency virus (HIV) transmission via blood or tissues that has occurred since anti-HIV screening was implemented in 1985 is traceable to blood given after infection but before antibody seroconversion, a time that is referred to as the window period. In this study, the performance of newer assays designed to detect viral and serologic markers soon after infection is assessed, and the reduction in the window period achieved by these assays is estimated.

Study design and methods: Three cohort studies of persons at high risk for acquiring HIV infection were identified. These studies included well-controlled HIV type 1 (HIV-1) polymerase chain reaction (PCR) analyses of serial preseroconversion specimens from HIV-1-seroconverting homosexual men or intravenous drug users. Of 81 enrollees with anti-HIV-1 seroconversion documented by a viral lysate anti-HIV-1 enzyme immunosorbent assay (EIA) available in 1989, 13 (16%) had PCR-positive preseroconversion specimens. In the present study, sera from these 13 PCR-positive samples were further tested for anti-HIV by 10 contemporary EIAs and 6 supplemental assays, as well as being tested for plasma p24 antigen and HIV-1 RNA. Preseroconversion sera from 38 HIV-1 DNA PCR-negative cohort participants were also tested by selected anti-HIV EIAs and tested for p24 antigen and HIV-1 RNA. On the basis of these laboratory data and the intervals between blood drawing in all 81 men, the reduction in the preseroconversion window period achieved by these new assays was estimated with a mathematical model developed to analyze seroconversion data.

Results: Nine (69%) of the 13 preseroconversion PCR-positive samples had anti-HIV that was detectable by one or more contemporary anti-HIV-1 or anti-HIV type 2 EIA. Supplemental antibody assays were negative on all four EIA-nonreactive preseroconversion samples and negative or indeterminate on a high proportion of the nine EIA-reactive PCR-positive samples. Eight (61%) of the 13 samples were p24 antigen-positive, and 11 (85%) were HIV-1 RNA-positive. The estimated reductions in the window period (relative to the index viral lysate-based anti-HIV EIA) were as follows: contemporary anti-HIV-1/2 EIAs, 20.3 days (95% Cl, 8.0-32.5); p24 antigen and DNA PCR, 26.4 days (95% Cl, 12.6-38.7); and RNA PCR, 31.0 days (95% Cl, 16.7-45.3).

Conclusion: Recent improvement in the sensitivity of anti-HIV assays has resulted in significant shortening of the preseroconversion window period. Consequently, the incremental reduction in the window period that could be achieved by implementing direct virus-detection assays has diminished significantly.

The identification of recent HIV-1 infection is clinically important for the effective treatment and prevention of transmission. However, the window period for seroconversion with respect to various HIV-1 antibodies is not well characterized. In addition, the routine HIV testing algorithms are not particularly appropriate for the identification of recent HIV-1 infection. In this study, we enrolled individuals who showed seroconversion from negative Western blot (WB) or indeterminate WB results and analyzed the window periods for appearance of HIV-1 antibodies. A total of 10,934 individuals with suspected HIV infection were tested by Wuhan CDC between 2012 and 2017; of these, 40 individuals with initial negative WB and 102 individuals with initial indeterminate WB who showed positive WB results within 100 days were included in the analysis. The mean time for seroconversion was 43.90 (95% confidence interval [CI]: 37.30–50.50) days and 42.15 (95% CI: 37.99–46.30) days, respectively. The time duration for p31 seroconversion among people with negative WB and indeterminate WB was 58.11 (95% CI, 44.30–71.92) days and 51.91 (95% CI, 44.55–59.28) days, respectively, both of which were significantly longer (p = 0.0169) than those in people without p31 seroconversion. A similar difference was observed with respect to p66 seroconversion, with a window time of 53.53 (95% CI, 43.54–63.52) days and 47.87 (95% CI, 43.16–52.57) days among people with negative WB and indeterminate WB, respectively. These data suggest that HIV-1 antibody p66, like p31, may serve as a potential serological marker for distinguishing Fiebig stage V and stage VI at day 70 post-infection.

Seroconversion And Viral Markers
Seroconversion And Viral Markers

Critique

SCR has high precision and accuracy, although its accuracy may decline at very low or high transmission levels. A strong advantage of SCR is the ability to reconstruct the history of exposure, which is especially useful in the common situation of missing baseline data (Corran et al., 2007). With regard to measuring a change in transmission, it has not been established whether SCR can measure less than log-fold differences in transmission (Drakeley et al., 2005b). Currently, SCR is not sensitive to short-term changes in transmission since antibodies can persist for years after the period of exposure, so it is necessary to wait for the population to age (Corran et al., 2007). However, some studies have reported SCR in the youngest children (< 5 years) (Ceesay et al., 2010) and this is a method for making SCR estimates more useful for determining recent yearly reductions in transmission intensity. Antigens that prove useful components of malaria vaccines may become redundant in SCR assays if such a vaccine becomes widely used (Corran et al., 2007). Fluctuations in recent exposure can also be determined by examining antibody titres, since seropositivity can last for many years, with currently infected individuals having the highest antibody responses and levels slowly declining as parasites are reduced. The frequency distribution of antibody titres can therefore be used to describe endemicity if titres are drawn from an age-representative cross-sectional survey (Cook and Drakeley, 2009; Kagan et al., 1969; Lobel et al., 1973). Compared to antibody prevalence, antibody titres will have greater discriminatory power where transmission is high and when a very sensitive assay is used

Introduction

HIV/AIDS continues to be a major global public health crisis with wide social ramifications. In the year 2017, an estimated 1.8 million new cases of HIV infection and 0.94 million HIV-related deaths were reported across the world (World Health Organization [WHO], 2017). Given the UNAIDS 90-90-90 target to end AIDS in 2030 (Brostrom et al., 2014), expansion of the access to HIV testing and improvement in screening algorithms is a key imperative, and the increasing detection of recent HIV-1 infection in clinical practice has posed to be a major challenge (Schupbach et al., 2007; Cohen et al., 2010; Branson and Stekler, 2012; Liu et al., 2016; Bottone and Bartlett, 2017; Ning et al., 2018; Toussova et al., 2018). Recent HIV-1 infection, also known as early HIV-1 infection or primary HIV-1 infection, is usually defined as detectable HIV-1 RNA or p24 antigen in serum or plasma in the setting of negative or indeterminate result of HIV-1 antibody test including Western blot (WB) (Pilcher et al., 2010). Recent HIV-1 infection can be confirmed by subsequent HIV antibody seroconversion. The identification of recent HIV-1 infection is extremely useful for antiretroviral treatment and for pathogenetic and epidemiologic studies (Cohen et al., 2010; Hecht et al., 2011).

According to the staging of recent HIV-1 infection by Fiebig et al. (2003) (Cohen et al., 2011b), the progression of HIV-1 infection can be divided into six separate stages based on the results of sequential laboratory tests. Of these, the fourth-generation assays for detection of HIV-1 and HIV-2 antibodies (Ab) and HIV-1 p24 antigen (Ag) can be used to detect HIV infection after the eclipse phase and stage I, while results of WB are negative in stage II and III, and indeterminate in stage IV. In stage V (day 31–100 post-infection), HIV-1 antibodies that bind to fixed viral proteins would result in WB reactive, while p31 band remains non-reactive (Fiebig et al., 2003; Cohen et al., 2010, 2011b). Several studies have found that the pattern of WB bands is associated with recent HIV-1 infection (Schupbach et al., 2007, 2011; Wang et al., 2013) and disease progression (Garland et al., 1996). For example, p31 can be used as a viral marker to distinguish Fiebig stage V and stage VI (Cohen et al., 2011b). In a study by Sudha et al. (2006), p31 was the most frequently missing band, followed by p55, p66, p51, and gp41. The emergence of HIV-1 WB bands at different time-points during the early infection may reflect the interaction between the virus and the host. However, data pertaining to seroconversion duration for each HIV-1 antibody are limited and the relation of various WB bands with disease progression is not well characterized. In order to further understand the window period for appearance of HIV-1 antibodies, we retrospectively analyzed the seroconversion time of individuals with recent HIV-1 infection in Wuhan, China.

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