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1.  Estimating HIV Incidence in Populations Using Tests for Recent Infection: Issues, Challenges and the Way Forward 
Introduction
HIV incidence is the rate of new infections in a population over time. HIV incidence is a critical indicator needed to assess the status and trends of the HIV epidemic in populations and guide and assess the impact of prevention interventions.
Methods
Several methods exist for estimating population-level HIV incidence: direct observation of HIV incidence through longitudinal follow-up of persons at risk for new HIV infection, indirect measurement of HIV incidence using data on HIV prevalence and mortality in a population, and direct measurement of HIV incidence through use of tests for recent infection (TRIs) that can differentiate “recent” from “non-recent” infections based on biomarkers in cross-sectional specimens. Given the limitations in measuring directly observed incidence and the assumptions needed for indirect measurements of incidence, there is an increasing demand for TRIs for HIV incidence surveillance and program monitoring and evaluation purposes.
Results
Over ten years since the introduction of the first TRI, a number of low-, middle-, and high-income countries have integrated this method into their HIV surveillance systems to monitor HIV incidence in the population. However, the accuracy of these assays for measuring HIV incidence has been unsatisfactory to date, mainly due to misclassification of chronic infections as recent infection on the assay. To improve the accuracy of TRIs for measuring incidence, countries are recommended to apply case-based adjustments, formula-based adjustments using local correction factors, or laboratory-based adjustment to minimize error related to assay misclassification. Multiple tests may be used in a recent infection testing algorithm (RITA) to obtain more accurate HIV incidence estimates.
Conclusion
There continues to be a high demand for improved TRIs and RITAs to monitor HIV incidence, determine prevention priorities, and assess impact of interventions. Current TRIs have noted limitations, but with appropriate adjustments, interpreted in parallel with other epidemiologic data, may still provide useful information on new infections in a population. New TRIs and RITAs with improved accuracy and performance are needed and development of these tools should be supported.
PMCID: PMC3130510  PMID: 21743821
2.  Preexposure Prophylaxis for HIV Infection among African Women 
The New England journal of medicine  2012;367(5):411-422.
BACKGROUND
Preexposure prophylaxis with antiretroviral drugs has been effective in the prevention of human immunodeficiency virus (HIV) infection in some trials but not in others.
METHODS
In this randomized, double-blind, placebo-controlled trial, we assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine (TDF–FTC) or placebo once daily. The primary objective was to assess the effectiveness of TDF–FTC in preventing HIV acquisition and to evaluate safety.
RESULTS
HIV infections occurred in 33 women in the TDF–FTC group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval, 0.59 to 1.52; P = 0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the TDF–FTC group (P = 0.04, P<0.001, and P = 0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the TDF–FTC group (4.7%) than in the placebo group (3.0%, P = 0.051). Less than 40% of the HIV-uninfected women in the TDF–FTC group had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. The study was stopped early, on April 18, 2011, because of lack of efficacy.
CONCLUSIONS
Prophylaxis with TDF–FTC did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite substantial counseling efforts, drug adherence appeared to be low. (Supported by the U.S. Agency for International Development and others; FEM-PrEP ClinicalTrials.gov number, NCT00625404.)
doi:10.1056/NEJMoa1202614
PMCID: PMC3687217  PMID: 22784040
3.  HIV Surveillance in a Large, Community-Based Study: Results from the Pilot Study of Project Accept (HIV Prevention Trials Network 043) 
BMC Infectious Diseases  2011;11:251.
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.
doi:10.1186/1471-2334-11-251
PMCID: PMC3198953  PMID: 21943026
4.  Addressing HIV prevention research priorities in the United States 
More than half a million Americans became newly infected with HIV in the first decade of the new millennium. The domestic epidemic has had the heaviest impact on men who have sex with men (MSM) and people from racial and ethnic minority populations, particularly African-Americans. For example, Black MSM represent <1% of the U.S. population but 25% of the new HIV cases, as per CDC estimates published in 2008. While Black and Hispanic women constitute 24% of all U.S. women, they accounted for 82% of HIV cases in women in 2005, based on data from 33 states with confidential name-based reporting. There is a nearly 23-fold higher rate of AIDS diagnoses for Black women (45.5/100,000 women) and nearly 6-fold higher rate for Hispanic women (11.2/100,000) compared to the rate for white women (2.0/100,000). Investigators from the HIV Prevention Trials Network (HPTN), an NIH-sponsored collaborative clinical trials group, have crafted a domestic research agenda with community input. Two new domestic studies are in progress (2009) and a community-based clinical trial feasibility effort is in development (2010 start date). These studies focus on outreach, testing, and treatment of infected persons as a backbone for HIV prevention. Reaching persons not receiving health message and service with novel approaches to both prevention and care/treatment is an essential priority for HIV control in the U.S.; our research is designed to guide the best approaches and assess the impact of bridging treatment and prevention.
doi:10.1086/651485
PMCID: PMC2862583  PMID: 20397942
HIV; prevention; United States; homosexual; women; transmission; antiretroviral treatment; black; Hispanic
5.  Male Circumcision in the United States for the Prevention of HIV Infection and Other Adverse Health Outcomes: Report from a CDC Consultation 
Public Health Reports  2010;125(Suppl 1):72-82.
SYNOPSIS
In April 2007, the Centers for Disease Control and Prevention (CDC) held a two-day consultation with a broad spectrum of stakeholders to obtain input on the potential role of male circumcision (MC) in preventing transmission of human immunodeficiency virus (HIV) in the U.S. Working groups summarized data and discussed issues about the use of MC for prevention of HIV and other sexually transmitted infections among men who have sex with women, men who have sex with men (MSM), and newborn males. Consultants suggested that (1) sufficient evidence exists to propose that heterosexually active males be informed about the significant but partial efficacy of MC in reducing risk for HIV acquisition and be provided with affordable access to voluntary, high-quality surgical and risk-reduction counseling services; (2) information about the potential health benefits and risks of MC should be presented to parents considering infant circumcision, and financial barriers to accessing MC should be removed; and (3) insufficient data exist about the impact (if any) of MC on HIV acquisition by MSM, and additional research is warranted. If MC is recommended as a public health method, information will be required on its acceptability and uptake. Especially critical will be efforts to understand how to develop effective, culturally appropriate public health messages to mitigate increases in sexual risk behavior among men, both those already circumcised and those who may elect MC to reduce their risk of acquiring HIV.
PMCID: PMC2788411  PMID: 20408390
6.  Blood and Seminal Plasma HIV-1 RNA Levels among HIV-1-infected Injecting Drug Users Participating in the AIDSVAX B/E Efficacy Trial in Bangkok, Thailand 
Background
We investigated effects of vaccination with AIDSVAX B/E HIV-1 candidate vaccine on blood and seminal plasma HIV-1 ribonucleic acid viral load (BVL and SVL, respectively) in vaccine recipients (VR) and placebo recipients (PR) who acquired infection.
Methods
Linear mixed models were fitted for repeated measurements of BVL. Generalized estimating equations were used to assess the difference in SVL detectability between VR and PR.
Results
A total of 196 participants became HIV-1 infected during the trial. Thirty-two (16%) became infected with HIV-1 subtype B and 164 (84%) with HIV-1 subtype CRF01_AE. Per protocol-specified analysis, there were no differences in BVL levels between VR and PR. When stratified by HIV-1-infecting subtype, vaccination with AIDSVAX B/E was initially associated with higher BVL among HIV-1 CRF01_AE-infected VR compared to HIV-1 CRF01_AE-infected PR, however, this difference did not persist over time. HIV-1 subtype B-infected VR had slightly higher BVL levels and were more likely to have detectable SVL during the follow-up period than HIV-1 subtype B-infected PR.
Conclusions
Subtle differences in BVL and SVL were detected between VR and PR. These results may help to further understand the dynamics between HIV-1 vaccination, HIV-1-infecting subtypes, and subsequent viral expression in different body compartments.
doi:10.1097/QAI.0b013e3181a44700
PMCID: PMC2764047  PMID: 19430307
HIV-1 vaccine; HIV-1 RNA viral load; Injecting drug users
8.  Male Circumcision for Prevention of HIV Transmission: What the New Data Mean for HIV Prevention in the United States 
PLoS Medicine  2007;4(7):e223.
Recent clinical trials in Africa found that male circumcision reduces the risk of acquiring HIV from heterosexual sex--what are the implications of these studies for the United States?
doi:10.1371/journal.pmed.0040223
PMCID: PMC1925125  PMID: 17676944
9.  Intersubtype Human Immunodeficiency Virus Type 1 Superinfection following Seroconversion to Primary Infection in Two Injection Drug Users 
Journal of Virology  2002;76(15):7444-7452.
In this study, we describe two cases of human immunodeficiency virus type 1 (HIV-1) intersubtype superinfection with CRF01_AE and subtype B strains, which occurred in two injection drug users participating in a prospective cohort study in Bangkok, Thailand. In both cases, the superinfecting strain was detected by molecular and serologic analyses several weeks after complete seroconversion to the primary infection with a strain belonging to a different subtype. Superinfection occurred despite specific T-cell and humoral antibody responses to the primary virus. In both cases, cross-subtype immune responses were limited or absent prior to the second infection. These data show that, in some individuals, the quality and quantity of the immune response elicited by primary HIV-1 infection may not protect against superinfection. This finding has important implications for vaccine design. HIV-1 vaccines, at a minimum, will need to include potent, broadly protective, conserved immunogens derived from several group M subtypes.
doi:10.1128/JVI.76.15.7444-7452.2002
PMCID: PMC136380  PMID: 12097556
10.  Evaluation of United States-Licensed Human Immunodeficiency Virus Immunoassays for Detection of Group M Viral Variants 
Journal of Clinical Microbiology  2001;39(3):1017-1020.
Six Food and Drug Administration (FDA)-licensed human immunodeficiency virus type 1 (HIV-1) and HIV-1/2 immunoassays, including five enzyme immunoassays and one rapid test, were challenged with up to 250 serum samples collected from various global sites. The serum samples were from individuals known to be infected with variants of HIV-1 including group M subtypes A, B, B′, C, D, E, F, and G and group O. All immunoassays detected the vast majority of samples tested. Three samples produced low signal over cutoff values in one or more tests: a clade B sample, an untypeable sample with a low antibody titer, and a group O sample. It is concluded that HIV-1 immunoassays used in the United States are capable of detecting most HIV-1 group M variants.
doi:10.1128/JCM.39.3.1017-1020.2001
PMCID: PMC87866  PMID: 11230420
11.  Analysis of Genetic Variability within the Immunodominant Epitopes of Envelope gp41 from Human Immunodeficiency Virus Type 1 (HIV-1) Group M and Its Impact on HIV-1 Antibody Detection 
Journal of Clinical Microbiology  2000;38(2):773-780.
The serodiagnosis of human immunodeficiency virus type 1 (HIV-1) infection primarily relies on the detection of antibodies, most of which are directed against the immunodominant regions (IDR) of HIV-1 structural proteins. Among these, the N-terminal region of gp41 contains cluster I (amino acids [aa] 580 to 623), comprising the cytotoxic T-lymphocyte epitope (AVERYLKDQQLL) and the cysteine loop (CSGKLIC), and cluster II (aa 646 to 682), comprising an ectodomain region (ELDKWA). To delineate the epitope diversity within clusters I and II and to determine whether the diversity affects serologic detection by U.S. Food and Drug Administration (FDA)-licensed enzyme immunoassay (EIA) kits, gp41 Env sequences from 247 seropositive persons infected with HIV-1 group M, subtypes A (n = 42), B (n = 62), B′ (n = 13), C (n = 38), D (n = 41), E (n = 18), F (n = 27), and G (n = 6), and 6 HIV-1-infected but persistently seronegative (HIPS) persons were analyzed. While all IDR were highly conserved among both seropositive and HIPS persons, minor amino acid substitutions (<20% for any one residue, mostly conservative) were observed for all subtypes, except for B′, in comparison with the consensus sequence for each subtype. Most importantly, none of the observed substitutions among the group M plasma specimens affected antibody detection, since all specimens (n = 152) tested positive with all five FDA-licensed EIA kits. Furthermore, all specimens reacted with a group M consensus gp41 peptide (WGIKQLQARVLAVERYLKDQQLLGIWGCSGKLICTTAVPWNASW), and high degrees of cross-reactivity (>80%) were observed with an HIV-1 group N peptide, an HIV-1 group O peptide, and a peptide derived from the homologous region of gp41 from simian immunodeficiency virus from chimpanzee (SIVcpz). Taken together, these data indicate that the minor substitutions observed within the IDR of gp41 of HIV-1 group M subtypes do not affect antibody recognition and that all HIV-1-seropositive specimens containing the observed substitutions react with the FDA-licensed EIA kits regardless of viral genotype and geographic origin.
PMCID: PMC86201  PMID: 10655384
12.  Detection of Phylogenetically Diverse Human Immunodeficiency Virus Type 1 Groups M and O from Plasma by Using Highly Sensitive and Specific Generic Primers 
Journal of Clinical Microbiology  1999;37(8):2581-2586.
The high degree of genetic diversity within human immunodeficiency virus type 1 (HIV-1), which includes two major groups, M (major) and O (outlier), and various env subtypes within group M (subtypes A to J), has made designing assays that will detect all known HIV-1 strains difficult. We have developed a generic primer set based on the conserved immunodominant region of transmembrane protein gp41 that can reliably amplify as few as 10 copies/PCR of viral DNA from near-full-length clones representing group M subtypes A to H (subtypes I and J were not available). The assay is highly sensitive in detecting plasma viral RNA from HIV-1 strains of diverse geographic origins representing different subtypes of HIV-1 group M as well as HIV-1 group O. Of the 253 group M plasma specimens (subtypes A, 68 specimens; B, 71; C, 19; D, 27; E, 23; F, 33; and G, 12), 250 (98.8%) were amplified by using the gp41 M/O primer set. More importantly, all 32 (100%) group O plasma samples were also amplified with these primers. In vitro spiking experiments further revealed that the assay could reliably detect as few as 25 copies/ml of viral RNA and gave positive signals in HIV-1-seropositive specimens with plasma copy numbers below the limits of detection by all commercially available viral load assays. In addition, analysis of five seroconversion panels indicated that the assay is highly sensitive for early detection of plasma viremia during the “window period.” Thus, the highly sensitive assay will be useful for early detection of HIV-1 in clinical specimens from all known HIV-1 infections, regardless of their genotypes and geographic origins.
PMCID: PMC85288  PMID: 10405405

Results 1-12 (12)