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Viral suppression and viral breakthrough impact the humoral immune response to HIV infection. We evaluated the impact of viral suppression and viral breakthrough on results obtained with two cross-sectional HIV incidence assays. All samples were collected from adults in the US who were HIV infected for >2 years. Samples were tested with the BED capture enzyme immunoassay (BED-CEIA) which measures the proportion of IgG that is HIV-specific, and with an antibody avidity assay based on the Genetic Systems 1/2+ O ELISA. We tested 281 samples: (1) 30 samples from 18 patients with natural control of HIV-1 infection known as elite controllers or suppressors (2) 72 samples from 18 adults on antiretroviral therapy (ART), with 1 sample before and 2-6 samples after ART initiation, and (3) 179 samples from 20 virally-suppressed adults who had evidence of viral breakthrough receiving ART (>400 copies/ml HIV RNA) and with subsequent viral suppression. For elite suppressors, 10/18 had BED-CEIA values <0.8 normalized optical density units (OD-n) and these values did not change significantly over time. For patients receiving ART, 14/18 had BED-CEIA values that decreased over time, with a median decrease of 0.42 OD-n (range 0.10 to 0.63)/time point receiving ART. Three patterns of BED-CEIA values were observed during viral breakthrough: (1) values that increased then returned to pre-breakthrough values when viral suppression was re-established, (2) values that increased after viral breakthrough, and (3) values that did not change with viral breakthrough. Viral suppression and viral breakthrough were associated with changes in BED-CEIA values, reflecting changes in the proportion of HIV-specific IgG. These changes can result in misclassification of patients with long-term HIV infection as recently infected using the BED-CEIA, thereby influencing a falsely high value for cross-sectional incidence estimates.

The Post-exposure Prophylaxis in Infants (PEPI)-Malawi trial evaluated infant antiretroviral regimens for prevention of post-natal HIV transmission. A multi-assay algorithm (MAA) that includes the BED capture immunoassay, an avidity assay, CD4 cell count, and viral load was used to identify women who were vs. were not recently infected at the time of enrollment (MAA recent, N = 73; MAA non-recent, N = 2,488); a subset of the women in the MAA non-recent group known to have been HIV infected for at least 2 years before enrollment (known non-recent, N = 54). Antibody maturation and viral diversification were examined in these women. Samples collected at enrollment (N = 2,561) and 12-24 months later (N = 1,306) were available for serologic analysis using the BED and avidity assays. A subset of those samples was used for analysis of viral diversity, which was performed using a high resolution melting (HRM) diversity assay. Viral diversity analysis was performed using all available samples from women in the MAA recent group (61 enrollment samples, 38 follow-up samples) and the known non-recent group (43 enrollment samples, 22 follow-up samples). Diversity data from PEPI-Malawi were also compared to similar data from 169 adults in the United States (US) with known recent infection (N = 102) and known non-recent infection (N = 67). In PEPI-Malawi, results from the BED and avidity assays increased over time in the MAA recent group, but did not change significantly in the MAA non-recent group. At enrollment, HIV diversity was lower in the MAA recent group than in the known non-recent group. HRM diversity assay results from women in PEPI-Malawi were similar to those from adults in the US with known duration of HIV infection. Antibody maturation and HIV diversification patterns in African women provide additional support for use of the MAA to identify populations with recent HIV infection.

Background. Accurate testing algorithms are needed for estimating human immunodeficiency virus (HIV) incidence from cross-sectional surveys. Methods. We developed a multiassay algorithm (MAA) for HIV incidence that includes the BED capture enzyme immunoassay (BED-CEIA), an antibody avidity assay, HIV load, and CD4⁺ T-cell count. We analyzed 1782 samples from 709 individuals in the United States who had a known duration of HIV infection (range, 0 to >8 years). Logistic regression with cubic splines was used to compare the performance of the MAA to the BEDCEIA and to determine the window period of the MAA. We compared the annual incidence estimated with the MAA to the annual incidence based on HIV seroconversion in a longitudinal cohort. Results. The MAA had a window period of 141 days (95% confidence interval [CI], 94-150) and a very low false-recent misclassification rate (only 0.4% of 1474 samples from subjects infected for >1 year were misclassified as indicative of recent infection). In a cohort study, annual incidence based on HIV seroconversion was 1.04% (95% CI, .70%-1.55%). The incidence estimate obtained using the MAA was essentially identical: 0.97% (95% CI, .5196-1.71%). Conclusions. The MAA is as sensitive for detecting recent HIV infection as the BED-CEIA and has a very low rate of false-recent misclassification. It provides a powerful tool for cross-sectional HIV incidence determination.

The prevalence of hepatitis C virus (HCV) infection in sub-Saharan Africa remains unclear. We tested 1000 individuals from Rakai, Uganda, with the Ortho version 3.0 HCV enzyme-linked immunosorbent assay. All serologically positive samples were tested for HCV RNA. Seventy-six of the 1000 (7.6%) participants were HCV antibody positive; none were confirmed by detection of HCV RNA.

Background Project Accept is a community randomized, controlled trial to evaluate the efficacy of community mobilization, mobile testing, same-day results, and post-test support for the prevention of HIV infection in Thailand, Tanzania, Zimbabwe, and South Africa. We evaluated the accuracy of in-country HIV rapid testing and determined HIV prevalence in the Project Accept pilot study. Methods Two HIV rapid tests were performed in parallel in local laboratories. If the first two rapid tests were discordant (one reactive, one non-reactive), a third HIV rapid test or enzyme immunoassay was performed. Samples were designated HIV NEG if the first two tests were non-reactive, HIV DISC if the first two tests were discordant, and HIV POS if the first two tests were reactive. Samples were re-analyzed in the United States using a panel of laboratory tests. Results HIV infection status was correctly determined based on-in country testing for 2,236 (99.5%) of 2,247 participants [7 (0.37%) of 1,907 HIV NEG samples were HIV-positive; 2 (0.63%) of 317 HIV POS samples were HIV-negative; 2 (8.3%) of 24 HIV DISC samples were incorrectly identified as HIV-positive based on the in-country tie-breaker test]. HIV prevalence was: Thailand: 0.6%, Tanzania: 5.0%, Zimbabwe 14.7%, Soweto South Africa: 19.4%, Vulindlela, South Africa: 24.4%, (overall prevalence: 14.4%). Conclusions In-country testing based on two HIV rapid tests correctly identified the HIV infection status for 99.5% of study participants; most participants with discordant HIV rapid tests were not infected. HIV prevalence varied considerably across the study sites (range: 0.6% to 24.4%). Trial Registration ClinicalTrials.gov registry number NCT00203749 .

Background. Human immunodeficiency virus (HIV) superinfection has been documented in high-risk individuals; however, the rate of superinfection among HIV-infected individuals within a general population remains unknown. Methods. A novel next-generation ultra-deep sequencing technique was utilized to determine the rate of HIV superinfection in a heterosexual population by examining two regions of the viral genome in longitudinal samples from recent HIV seroconverters (n = 149) in Rakai District, Uganda. Results. The rate of superinfection was 1.44 per 100 person years (PYs) (95% confidence interval [CI], .4-2.5) and consisted of both inter- and intrasubtype superinfections. This was compared to primary HIV incidence in 20 220 initially HIV-negative individuals in the general population in Rakai (1.15 per 100 PYs; 95% CI, 1.1-1.2; P = .26). Propensity score matching (PS) was used to control for differences in sociodemographic and behavioral characteristics between the HIV-positive individuals at risk for superinfection and the HIV-negative population at baseline and follow-up. After PS matching, the estimated rate of primary incidence was 3.28 per 100 PYs (95% CI, 2.0-5.3; P = .07) controlling for baseline differences and 2.51 per 100 PYs (95% CI, 1.5-4.3; P = .24) controlling for follow-up differences. Conclusions. This suggests that the rate of HIV superinfection in a general population is substantial, which could have a significant impact on future public health and HIV vaccine strategies.

Background. A genetic bottleneck is known to exist for human immunodeficiency virus (HIV) at the point of sexual transmission. However, the nature of this bottleneck and its effect on viral diversity over time is unclear. Methods. Interhost and intrahost HIV diversity was analyzed in a stable population in Rakai, Uganda, from 1994 to 2002. HIV-1 envelope sequences from both individuals in initially HIV-discordant relationships in which transmission occurred later were examined using Sanger sequencing of bulk polymerase chain reaction (PCR) products (for 22 couples), clonal analysis (for 3), and next-generation deep sequencing (for 9). Results. Intrahost viral diversity was significantly higher than changes in interhost diversity (P<.01). The majority of HIV-1-discordant couples examined via bulk PCR (16 of 22 couples), clonal analysis (3 of 3), and next-generation deep sequencing (6 of 9) demonstrated that the viral populations present in the newly infected recipient were more closely related to the donor partner's HIV-1 variants found earlier during infection as compared to those circulating near the estimated time of transmission (P = .03). Conclusions. These findings suggest that sexual transmission constrains viral diversity at the population level, partially because of the preferential transmission of ancestral as opposed to contemporary strains circulating in the transmitting partner. Future successful vaccine strategies may need to target these transmitted ancestral strains.

Background. Reliable methods for estimating the incidence of human immunodeficiency virus (HIV) infection are needed to monitor the epidemic, identify at-risk populations, and evaluate HIV prevention strategies. We used a multifaceted approach to estimate HIV incidence in the HIV Prevention Trials Network (HPTN) 064 study. Methods. The HPTN 064 study enrolled 2067 HIV-seronegative women and 32 HIV-seropositive women with no prior HIV infection diagnosis. Women were followed for up to 12 months. HIV incidence estimates were based on (1) detection of acute HIV infection, (2) documentation of HIV seroconversion, and (3) detection of recent HIV infection, using a multiassay algorithm (MAA). Results. Two women had acute HIV infection at enrollment, 4 seroconverted, and 2 were identified as recently infected at enrollment using the MAA. The annual HIV incidence estimate based on acute infection at enrollment (2.52% [95% confidence interval {CI}, .17%-9.33%], using a 14-day window period) was higher than the estimate based on seroconversion (0.24% [95% CI, .07%-. 62%]; P= .027). Incidence estimates obtained using the MAA at enrollment and at the end of study were 0.25% (95% CI, .03%-. 93%) and 0.13% (95% CI, .006%-.76%), respectively. Conclusions. We detected a high frequency of acute infection at enrollment. Cross-sectional HIV incidence estimates obtained using the MAA were similar to the longitudinal estimate based on HIV seroconversion.

Background. Sensitive methods are needed to estimate the population-level incidence of hepatitis C virus (HCV) infection. Methods. We developed an HCV immunoglobulin G (IgG) antibody avidity assay by modifying the Ortho 3.0 HCV enzymelinked immunoassay and tested 997 serum or plasma samples from 568 people who inject drugs enrolled in prospective cohort studies. Avidity-based testing algorithms were evaluated by their (1) mean duration of recent infection (MDRI), defined as the average time an individual is identified as having been recently infected, according to a given algorithm; (2) false-recent rate, defined as the proportion of samples collected > 2 years after HCV seroconversion that were misclassified as recent; (3) sample sizes needed to estimate incidence; and (4) power to detect a reduction in incidence between serial cross-sectional surveys. Results. A multiassay algorithm (defined as an avidity index of < 30%, followed by HCV viremia detection) had an MDRI of 147 days (95% confidence interval [C1], 125-195 days), and the false-recent rates were 0.7% (95% CI, .296-1.8%) and 7.6% (95% CI, 4.2%-12.3%) among human immunodeficiency virus (HIV)-negative and HIV-positive persons, respectively. In various simulated high-risk populations, this algorithm required < 1000 individuals to estimate incidence (relative standard error, 30%) and had > 80% power to detect a 50% reduction in incidence. Conclusions. Avidity-based algorithms have the capacity to accurately estimate HCV infection incidence and rapidly assess the impact of public health efforts among high-risk populations. Efforts to optimize this method should be prioritized.