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Acute/early HIV infection is a period of high HIV transmission. Consequently, early detection of HIV infection and targeted HIV prevention could prevent a significant proportion of new transmissions. As part of an NIMH-funded multisite study, we used in-depth interviews to explore understandings of acute HIV infection (AHI) among 34 individuals diagnosed with acute/early HIV infection in six U.S. cities. We found a marked lack of awareness of AHI-related acute retroviral symptoms and a lack of clarity about AHI testing methods. Most participants knew little about the meaning and/or consequences of AHI, particularly that it is a period of elevated infectiousness. Over time and after the acute stage of infection, many participants acquired understanding of AHI from varied sources, including the Internet, HIV-infected friends, and health clinic employees. There is a need to promote targeted education about AHI to reduce the rapid spread of HIV associated with acute/early infection within communities at risk for HIV.

Acute HIV infection (AHI) is the earliest stage of HIV disease, when plasma HIV viremia, but not HIV antibodies, can be detected. Acute HIV infection often presents as a nonspecific viral syndrome. However, its diagnosis, which enables linkage to early medical care and limits further HIV transmission, is seldom made. We describe the experience of Yale's Center for Interdisciplinary Research on AIDS with AHI diagnosis in Connecticut, as a participating center in the National Institute of Mental Health Multisite AHI Study. We sought to identify AHI cases by clinical referrals and by screening for AHI at two substance abuse care facilities and an STD clinic: We identified one case by referral and one through screening of 590 persons. Screening for AHI is feasible and probably cost effective. Primary care providers should include AHI in the differential diagnosis when patients present with a nonspecific viral syndrome.

Objective

Individuals with acute (preseroconversion) HIV infection (AHI) are important in the spread of HIV. The identification of AHI requires the detection of viral proteins or nucleic acids with techniques that are often unaffordable for routine use. To facilitate the efficient use of these tests, we sought to develop a risk score algorithm for identifying likely AHI cases and targeting the tests towards those individuals.

Design

A cross-sectional study of 1448 adults attending a sexually transmitted infections (STI) clinic in Malawi.

Methods

Using logistic regression, we identified risk behaviors, symptoms, HIV rapid test results, and STI syndromes that were predictive of AHI. We assigned a model-based score to each predictor and calculated a risk score for each participant.

Results

Twenty-one participants (1.45%) had AHI, 588 had established HIV infection, and 839 were HIV-negative. AHI was strongly associated with discordant rapid HIV tests and genital ulcer disease (GUD). The algorithm also included diarrhea, more than one sexual partner in 2 months, body ache, and fever. Corresponding predictor scores were 1 for fever, body ache, and more than one partner; 2 for diarrhea and GUD; and 4 for discordant rapid tests. A risk score of 2 or greater was 95.2% sensitive and 60.5% specific in detecting AHI.

Conclusion

Using this algorithm, we could identify 95% of AHI cases by performing nucleic acid or protein tests in only 40% of patients. Risk score algorithms could enable rapid, reliable AHI detection in resource-limited settings.

Combination testing with anti-HIV Elisa and Western blot is both sensitive and specific for diagnosis of established HIV-1 infection but could not detect acute HIV infection (AHI). AHI is a time of extremely high viral load, which may correlate to increased risk of horizontal or vertical transmission. Thus, early identification of AHI could allow for interventions to decrease transmission. However, recognition of AHI can be challenging as symptoms could be absent or nonspecific, therefore, AHI is often not detected, particularly in pregnancy. We present a case report of AHI in a pregnant woman who presented with headache and fever. She tested negative for HIV in the first trimester and at time of AHI at 26 3/7 weeks by anti-HIV Elisa, but was diagnosed with AHI based on an HIV RNA viral load of 434,000 copies/mL. This report presents a case for improved awareness of AHI in pregnancy, and the need for repeat HIV testing in late pregnancy, and highlighted that early detection of AHI might be possible with adding HIV RNA testing at time of standard anti-HIV Elisa screening test in pregnancy. Novel laboratory approaches including pooling of sera for HIV RNA could reduce the cost of HIV RNA testing.

Understanding sexual behavior following diagnosis of acute HIV infection (AHI) is key to developing prevention programs targeting individuals diagnosed with AHI. We conducted separate qualitative and quantitative interviews with individuals newly diagnosed (n = 19) with AHI at 1-, 4- and 12-weeks post-diagnosis and one qualitative interview with individuals who had previously been diagnosed with AHI (n = 18) in Lilongwe, Malawi and Johannesburg, South Africa between October 2007 and June 2008. The majority of participants reported engaging in sexual activity following diagnosis with AHI with a significant minority reporting unprotected sex during this time. Most participants perceived to have changed their behavior following diagnosis. However, participants reported barriers to condom use and abstinence, in particular, long term relationships and the need for disclosure of sero-status. Understanding of increased infectiousness during AHI was limited. Participants reported a desire for a behavioral intervention at the time of AHI diagnosis, however, there were differences by country in the types of interventions participants found acceptable. Studies are underway to determine the feasibility, acceptability and potential effectiveness of interventions designed for individuals with AHI.

Acute/early HIV infection is a period of heightened HIV transmission and a window of opportunity for intervention to prevent onward disease transmission. The NIMH Multisite Acute HIV Infection (AHI) Study was an exploratory initiative aimed at determining the feasibility of recruiting persons with AHI into research, assessing their psychosocial and behavioral characteristics, and examining short-term changes in these characteristics. This paper reports on lessons learned in the study, including: (1) the need to establish the cost-effectiveness of AHI testing; (2) challenges to identifying persons with AHI; (3) the need to increase awareness of acute-phase HIV transmission risks; (4) determining the goals of behavioral interventions following AHI diagnosis; and (5) the need for “rapid response” public health systems that can move quickly enough to intervene while persons are still in the AHI stage. There are untapped opportunities for behavioral and medical science collaborations in these areas that could reduce the incidence of HIV infection.

Purpose of Review

Acute HIV infection (AHI), the earliest period after HIV acquisition, is only a few weeks in duration. In this brief period, the concentration of HIV in blood and genital secretions is extremely high, increasing the probability of HIV transmission. Although a substantial role of AHI in the sexual transmission of HIV is biologically plausible, the significance of AHI in the epidemiological spread of HIV remains uncertain.

Recent Findings

AHI is diagnosed by detecting viral RNA or antigen in the blood of persons who are HIV seronegative. Depending on the setting, persons with AHI represent between 1% and 10% of persons with newly diagnosed HIV infection. The high concentration of virus during AHI leads to increased infectiousness, possibly as much as 26 times greater than during chronic infection. In mathematical models, the estimated proportion of transmission attributed to AHI has varied considerably, depending on model structure, model parameters and the population. Key determinants include the stage of the HIV epidemic and the sexual risk profile of the population.

Summary

Despite its brief duration, AHI plays a disproportionate role in the sexual transmission of HIV infection. Detection of persons with AHI may provide an important opportunity for transmission prevention.

Background

Acute HIV infection (AHI) is a critical phase of infection when irreparable damage to the immune system occurs and subjects are very infectious. We studied subjects with AHI prospectively to develop better treatment and public health interventions.

Methods

Cross-sectional screening was employed to detect HIV RNA positive, antibody negative subjects. Date of HIV acquisition was estimated from clinical history and correlated with sequence diversity assessed by single genome amplification (SGA). Twenty-two cytokines/chemokines were measured from enrollment through week 24.

Results

Thirty-seven AHI subjects were studied. In 7 participants with limited exposure windows, the median exposure to HIV occurred 14 days before symptom onset. Lack of viral sequence diversification confirmed the short duration of infection. Transmission dates estimated by SGA/sequencing using molecular clock models correlated with transmission dates estimated by symptom onset in individuals infected with single HIV variants (mean of 28 versus 33 days). Only 10 of 22 cytokines/chemokines were significantly elevated among AHI participants at enrollment compared to uninfected controls, and only 4 participants remained seronegative at enrollment.

Discussion

The results emphasize the difficulty in recruiting subjects early in AHI. Viral sequence diversity proved accurate in estimating time of infection. Regardless of aggressive screening, peak viremia and inflammation occurred before enrollment and potential intervention. Given the personal and public health importance, improved AHI detection is urgently needed.

CD8-mediated virus inhibition can be detected in HIV-1-positive subjects who naturally control virus replication. Characterizing the inhibitory function of CD8+ T cells during acute HIV-1 infection (AHI) can elucidate the nature of the CD8+ responses that can be rapidly elicited and that contribute to virus control. We examined the timing and HIV-1 antigen specificity of antiviral CD8+ T cells during AHI. Autologous and heterologous CD8+ T cell antiviral functions were assessed longitudinally during AHI in five donors from the CHAVI 001 cohort using a CD8+ T cell-mediated virus inhibition assay (CD8 VIA) and transmitted/founder (T/F) viruses. Potent CD8+ antiviral responses against heterologous T/F viruses appeared during AHI at the first time point sampled in each of the 5 donors (Fiebig stages 1/2 to 5). Inhibition of an autologous T/F virus was durable to 48 weeks; however, inhibition of heterologous responses declined concurrent with the resolution of viremia. HIV-1 viruses from 6 months postinfection were more resistant to CD8+-mediated virus inhibition than cognate T/F viruses, demonstrating that the virus escapes early from CD8+ T cell-mediated inhibition of virus replication. CD8+ T cell antigen-specific subsets mediated inhibition of T/F virus replication via soluble components, and these soluble responses were stimulated by peptide pools that include epitopes that were shown to drive HIV-1 escape during AHI. These data provide insights into the mechanisms of CD8-mediated virus inhibition and suggest that functional analyses will be important for determining whether similar antigen-specific virus inhibition can be induced by T cell-directed vaccine strategies.

Angela Hutchinson and colleagues conducted a cost-effectiveness analysis of pooled nucleic acid amplification testing following HIV testing and show that it is not cost-effective at recommended antibody testing intervals for high-risk persons except in very high-incidence settings.

Background

Detection of acute HIV infection (AHI) with pooled nucleic acid amplification testing (NAAT) following HIV testing is feasible. However, cost-effectiveness analyses to guide policy around AHI screening are lacking; particularly after more sensitive third-generation antibody screening and rapid testing.

Methods and Findings

We conducted a cost-effectiveness analysis of pooled NAAT screening that assessed the prevention benefits of identification and notification of persons with AHI and cases averted compared with repeat antibody testing at different intervals. Effectiveness data were derived from a Centers for Disease Control and Prevention AHI study conducted in three settings: municipal sexually transmitted disease (STD) clinics, a community clinic serving a population of men who have sex with men, and HIV counseling and testing sites. Our analysis included a micro-costing study of NAAT and a mathematical model of HIV transmission. Cost-effectiveness ratios are reported as costs per quality-adjusted life year (QALY) gained in US dollars from the societal perspective. Sensitivity analyses were conducted on key variables, including AHI positivity rates, antibody testing frequency, symptomatic detection of AHI, and costs. Pooled NAAT for AHI screening following annual antibody testing had cost-effectiveness ratios exceeding US$200,000 per QALY gained for the municipal STD clinics and HIV counseling and testing sites and was cost saving for the community clinic. Cost-effectiveness ratios increased substantially if the antibody testing interval decreased to every 6 months and decreased to cost-saving if the testing interval increased to every 5 years. NAAT was cost saving in the community clinic in all situations. Results were particularly sensitive to AHI screening yield.

Conclusions

Pooled NAAT screening for AHI following negative third-generation antibody or rapid tests is not cost-effective at recommended antibody testing intervals for high-risk persons except in very high-incidence settings.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Since 1981, acquired immunodeficiency syndrome (AIDS) has killed about 25 million people and about 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV, which is most often transmitted through unprotected sex with an infected partner or injection drug use, infects and kills immune system cells, leaving infected individuals susceptible to other infectious diseases. The first, often undiagnosed stage of HIV infection—acute HIV infection (AHI)—lasts a few weeks and sometimes involves a flu-like illness. During AHI, the immune system responds to HIV by beginning to make antibodies that recognize the virus but seroconversion—the appearance of detectable amounts of antibody in the blood—takes 6–12 weeks. During the second, symptom-free stage of HIV infection, which can last many years, the virus gradually destroys the immune system so that by the third stage of infection unusual infections (for example, persistent yeast infections) begin to occur. The final stage of infection (AIDS) is characterized by multiple severe infections and by the development of unusual cancers.

Why Was This Study Done?

Antiretroviral drugs control HIV infections but don't cure them. It is very important, therefore, to prevent HIV transmission by avoiding HIV risk behaviors that increase the risk of HIV infection such as having sex without a condom or with many partners. Individuals with AHI in particular need to avoid high-risk behaviors because these people are extremely infectious. However, routine tests for HIV infection that measure antibodies in the blood often give false-negative results in people with AHI because of the time lag between infection and seroconversion. Nucleic acid amplification testing (NAAT), which detects HIV genetic material in the blood, is a more accurate way to diagnose AHI but is expensive. In this study, the researchers investigate whether pooled NAAT screening (specimens are pooled before testing to reduce costs) for AHI in clinic settings after third-generation antibody testing is a cost-effective HIV prevention strategy. That is, does the gain in quality-adjusted life years (QALY, a measure of the quantity and quality of life generated by healthcare interventions) achieved by averting new HIV infections outweigh the costs of pooled NAAT screening?

What Did the Researchers Do and Find?

The researchers combined effectiveness data from a US study in which AHI was detected using pooled NAAT in three settings (sexually transmitted disease [STD] clinics, a community clinic serving men who have sex with men [MSM], and HIV counseling/testing sites) with a “micro-costing” study of NAAT and a mathematical model of HIV transmission. They then calculated the costs per QALY gained (the cost-effectiveness ratio) as a result of HIV prevention by identification and notification of people with AHI through pooled NAAT screening compared with repeat antibody testing. Pooled NAAT for AHI screening following annual antibody testing (the recommended testing interval for high-risk individuals), they estimate, would cost US$372,300 and US$484,400 per QALY gained for the counseling/testing sites and STD clinics, respectively, whereas pooled NAAT for AHI screening was cost-saving for the community clinic serving MSM. The cost-effectiveness ratio increased for the counseling/testing sites and STD clinics when the antibody testing interval was decreased to 6 months but remained cost-saving for the community clinic. With an antibody testing interval of 5 years, pooled NAAT was cost-saving in all three settings.

What Do These Findings Mean?

Cost-effectiveness ratios of US$100,000–US$200,000 are considered acceptable in the US. These results suggest therefore, that the cost of pooled NAAT screening for AHI following negative third-generation antibody testing is not acceptable at the recommended testing interval for high-risk individuals except in settings where HIV infection is very common such as clinics serving MSM. The researchers reach a similar conclusion in a separate cost-effectiveness analysis of pooled NAAT screening following a negative rapid HIV test. Although the accuracy of these results depends on numerous assumptions made in the cost-effectiveness analyses (for example, the degree to which awareness of HIV status affects the behavior of people with AHI), sensitivity analyses (investigations of the effect of altering key assumptions) show that these findings are not greatly affected by changes in many of these assumptions. Thus, the researchers conclude, NAAT screening should be reserved for settings that serve populations in which there are very high levels of new HIV infection.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000342.

The US Centers for Disease Control and Prevention provides information on HIV infection and AIDS and on HIV testing and diagnosis

HIV InSite has information on all aspects of HIV/AIDS

Information is available from Avert, an international AIDS nonprofit organization on many aspects of HIV/AIDS, including HIV testing (in English and Spanish)

MedlinePlus has links to further resources on AIDS (in English and Spanish)

The UK National Institute of Health and Clinical Excellence has a page on measuring effectiveness and cost-effectiveness

Objective

Characterize responses to a NNRTI-based antiretroviral treatment (ART) initiated during acute HIV infection (AHI).

Design

This was a prospective, single-arm evaluation of once daily, co-formulated emtricitabine/tenofovir/efavirenz initiated during AHI.

Methods

The primary endpoint is the proportion of responders with HIV RNA <200 copies/mL by week 24. We examined time-to-viral-suppression and CD8 cell activation in relation to baseline participant characteristics. We compared time-to-viral-suppression and viral dynamics using linear mixed effects models between acutely infected participants and chronically-infected controls.

Results

Between January 2005 and May 2009, 61 AHI participants were enrolled. Of participants whose enrollment date allowed 24 and 48 weeks of follow-up, 47 of 51 (92%) achieved viral suppression to <200 copies/mL by week 24, and 35 of 41 (85.4%) to <50 copies/mL by week 48. The median time from ART initiation to suppression <50 copies/mL was 93 days (range 14–337). Higher HIV RNA levels at ART initiation (p=0.02), but not time from estimated-date-of-infection to ART initiation (p=0.86), were associated with longer time-to-viral-suppression. The median baseline frequency of activated CD8+CD38+HLA-DR+ T-cells was 67% (range 40–95), and was not significantly associated with longer time to viral load suppression (p=0.15). Viremia declined to <50 copies/mL more rapidly in AHI than chronically-infected participants. Mixed model analysis demonstrated similar phase I HIV RNA decay rates between acute and chronically-infected participants, and more rapid viral decline in acutely-infected participants in phase II.

Conclusion

Once daily emtricitabine/tenofovir/efavirenz initiated during AHI achieves rapid and sustained HIV suppression during this highly infectious period.

Correctional systems increasingly serve as the health care nexus for the initial diagnosis and treatment of human immunodeficiency virus (HIV) infection, particularly among traditionally underserved populations. A survey was conducted to describe the clinical profile of inmates in a State correctional system diagnosed with HIV infection by various testing strategies. Approximately 50 percent of the inmates diagnosed were potential candidates for anti-retroviral therapy, and 17 percent were severely immunocompromised. Implementation of voluntary HIV testing at prison entry increased the number of persons identified with HIV infection; however, since volunteers at entry had higher CD4 cell counts compared with infected inmates diagnosed by other methods, there was not a parallel increase in the percentage requiring immediate medical treatment. These data are important for planning medical resources in the correctional setting and underscore the opportunity to provide prevention and therapy for a vulnerable population with HIV infection. Public health interventions within the correctional setting have a broader societal impact, since most infected inmates serve short sentences (median, 3 years). Clinical case management is critical for inmates with HIV infection released to the community so that linkages with primary care providers and support services can be established.

Background

Recent studies have shown the public health importance of identifying acute HIV infection (AHI) in the men who have sex with men (MSM) of China, which has a much higher risk of HIV transmission. However, cost-utility analyses to guide policy around AHI screening are lacking.

Methodology/Principal Findings

An open prospective cohort was recruited among MSM living in Liaoning Province, Northeast China. Blood samples and epidemiological information were collected every 10 weeks. Third-generation ELISA and rapid test were used for HIV antibody screening, western blot assay (WB) served for assay validation. Antibody negative specimens were tested with 24 mini-pool nucleic acid amplification testing (NAAT). Specimens with positive ELISA but negative or indeterminate WB results were tested with NAAT individually without mixing. A cost-utility analysis of NAAT screening was assessed. Among the 5,344 follow-up visits of 1,765 MSM in 22 months, HIV antibody tests detected 114 HIV chronic infections, 24 seroconverters and 21 antibody indeterminate cases. 29 acute HIV infections were detected with NAAT from 21 antibody indeterminate and 1,606 antibody negative cases. The HIV-1 prevalence and incidence density were 6.6% (95% CI: 5.5–7.9) and 7.1 (95% CI: 5.4–9.2)/100 person-years, respectively. With pooled NAAT and individual NAAT strategy, the cost of an HIV transmission averted was $1,480. The addition of NAAT after HIV antibody tests had a cost-utility ratio of $3,366 per gained quality-adjusted life year (QALY). The input-output ratio of NAAT was about 1∶16.9.

Conclusions/Significance

The HIV infections among MSM continue to rise at alarming rates. Despite the rising cost, adding pooled NAAT to the HIV antibody screening significantly increases the identification of acute HIV infections in MSM. Early treatment and target-oriented publicity and education programs can be strengthened to decrease the risk of HIV transmission and to save medical resources in the long run.

Objective

To evaluate HIV-1 RNA pooled nucleic acid amplification testing (NAAT) strategy to screen pregnant women in the “window period” of acute HIV infection (AHI) in rural South Africa.

Methods

In 2007 and 2008, 750 consecutive pregnant women at their first prenatal care visit to primary health care clinics were tested anonymously for HIV infection. HIV-1 RNA pooled NAAT was performed on HIV antibody negative samples. All positive pools were tested individually and positive samples were classified as incident cases to calculate HIV incidence.

Results

The overall HIV prevalence was 37.3% [95% confidence interval (CI) 34.3–41.3]. Of the 467 HIV antibody negative samples, four (0.9%) were HIV-1 RNA positive. The mean viral copies/ml in the four samples was 386260 (range 64 200 to 1228130). The HIV incidence was 11.2% per year (95% CI 0.3–22.1) and all women with AHI were ≤ 21 years of age.

Conclusions

Identifying AHI in pregnancy is important for health interventions to reduce perinatal and heterosexual transmission of HIV; and to estimate HIV incidence for epidemiological surveillance.

Recent studies have shown the public health importance of identifying individuals with acute human immunodeficiency virus infection (AHI); however, the cost of nucleic acid amplification testing (NAAT) makes individual testing of at-risk individuals prohibitively expensive in many settings. Pooled NAAT (or group testing) can improve efficiency and test performance of testing for AHI, but optimizing the pooling algorithm can be difficult. We developed simple, flexible biostatistical models of specimen pooling with NAAT for the identification of AHI cases; these models incorporate group testing theory, operating characteristics of biological assays, and a model of viral dynamics during AHI. Pooling algorithm sensitivity, efficiency (test kits used per individual specimen evaluated), and positive predictive value (PPV) were modeled and compared for three simple pooling algorithms: two-stage minipools (D2), three-stage hierarchical pools (D3), and square arrays with master pools (A2m). We confirmed the results by stochastic simulation and produced reference tables and a Web calculator to facilitate pooling by investigators without specific biostatistical expertise. All three pooling strategies demonstrated improved efficiency and PPV for AHI case detection compared to individual NAAT. D3 and A2m algorithms generally provided better efficiency and PPV than D2; additionally, A2m generally exhibited better PPV than D3. Used selectively and carefully, the simple models developed here can guide the selection of a pooling algorithm for the detection of AHI cases in a wide variety of settings.

Abstract

To provide evidence of large numbers of missed opportunities for early HIV diagnosis we designed a retrospective cohort study linking surveillance data from the South Carolina HIV/AIDS Reporting System to a statewide all payer health care database. We determined visits and diagnoses occurring before the date of the first positive HIV test and medical encounters were categorized to distinguish visits that were likely versus unlikely to have prompted an HIV test. Of the 4117 HIV-positive individuals newly diagnosed between 2001 and 2005, 3021 (73.4%) visited a South Carolina health care facility one or more times prior to testing HIV positive. Of these 3021, 1311 (43.4%) were late testers, and 1425 (47.2%) were early testers. Females were less likely than males to be late testers (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.45–0.68), blacks were more likely than whites to be late testers (OR 1.37, 95% CI 1.10–1.71), and persons 50 years of age and older more likely to be late testers (OR 7.16, 95% CI 3.84–13.37). A total of 78.8% of the 13,448 health care visits for both late and early testers were for health care diagnoses unlikely to prompt an HIV test. These findings underscore the need for more routine HIV testing of adults and adolescents visiting health care facilities in order to facilitate early diagnosis.

BACKGROUND:

Renal insufficiency, a common condition among patients with chronic heart failure, complicates the management of heart failure. However, the influence of renal insufficiency on sleep-disordered breathing (SDB) – another important comorbidity of heart failure – has not been well studied.

METHODS:

Seventy-nine patients (60 men and 19 women) with stable, symptomatic heart failure caused by left ventricular systolic dysfunction (left ventricular ejection fraction of less than 45%) were studied.

RESULTS:

Thirty-nine patients (49%) had SDB as defined by an apnea-hypopnea index (AHI) of five or greater: 15 patients were classified as having mild SDB (AHI of five or greater and less than 15), 10 patients as having moderate SDB (AHI of 15 or greater and less than 30) and 14 patients as having severe SDB (AHI of 30 or greater). The etiology of SDB was predominantly central. Plasma brain natriuretic peptide concentration in the severe SDB group was 587±377 pg/mL, which was significantly higher than those of the remaining three groups (P<0.05). On the other hand, estimated glomerular filtration rate (eGFR) was comparable between non-SDB and SDB groups. There was no statistically significant correlation between eGFR and AHI, or between eGFR and the number of central sleep apneas in the study patients.

CONCLUSION:

Higher plasma brain natriuretic peptide concentrations were associated with more severe SDB, whereas the level of eGFR was not correlated with the severity of SDB. The results suggest that renal dysfunction plays a relatively minor role in determining breathing abnormalities in chronic heart failure.

Background

At least 10% of the 56,000 annual new HIV infections in the United States are caused by individuals with acute HIV infection (AHI). It unknown whether the health benefits and costs of routine nucleic acid amplification testing (NAAT) are justified, given the availability of newer fourth-generation immunoassay tests.

Methods

Using a dynamic HIV transmission model instantiated with U.S. epidemiologic, demographic, and behavioral data, I estimated the number of acute infections identified, HIV infections prevented, quality-adjusted life years (QALYs) gained, and the cost-effectiveness of alternative screening strategies. I varied the target population (everyone aged 15-64, injection drug users [IDUs] and men who have sex with men [MSM], or MSM only), screening frequency (annually, or every six months), and test(s) utilized (fourth-generation immunoassay only, or immunoassay followed by pooled NAAT).

Results

Annual immunoassay testing of MSM reduces incidence by 9.5% and costs <$10,000 per QALY gained. Adding pooled NAAT identifies 410 AHI per year, prevents 9.6% of new cases, costs $92,000 per QALY gained, and remains <$100,000 per QALY gained in settings where undiagnosed HIV prevalence exceeds 4%. Screening IDUs and MSM annually with fourth-generation immunoassay reduces incidence by 13% with cost-effectiveness <$10,000 per QALY gained. Increasing the screening frequency to every six months reduces incidence by 11% (MSM only) or 16% (MSM and IDUs) and costs <$20,000 per QALY gained.

Conclusions

Pooled NAAT testing every 12 months of MSM and IDUs in the United States prevents a modest number of infections, but may be cost-effective given sufficiently high HIV prevalence levels. However, testing via fourth-generation immunoassay every six months prevents a greater number of infections, is more economically efficient, and may obviate the benefits of acute HIV screening via NAAT.

Understanding the interactions between human immunodeficiency virus type 1 (HIV-1) virions and antibodies (Ab) produced during acute HIV-1 infection (AHI) is critical for defining antibody antiviral capabilities. Antibodies that bind virions may prevent transmission by neutralization of virus or mechanically prevent HIV-1 migration through mucosal layers. In this study, we quantified circulating HIV-1 virion-immune complexes (ICs), present in approximately 90% of AHI subjects, and compared the levels and antibody specificity to those in chronic infection. Circulating HIV-1 virions coated with IgG (immune complexes) were in significantly lower levels relative to the viral load in acute infection than in chronic HIV-1 infection. The specificities of the antibodies in the immune complexes differed between acute and chronic infection (anti-gp41 Ab in acute infection and anti-gp120 in chronic infection), potentially suggesting different roles in immunopathogenesis for complexes arising at different stages of infection. We also determined the ability of circulating IgG from AHI to bind infectious versus noninfectious virions. Similar to a nonneutralizing anti-gp41 monoclonal antibody (MAb), purified plasma IgG from acute HIV-1 subjects bound both infectious and noninfectious virions. This was in contrast to the neutralizing antibody 2G12 MAb that bound predominantly infectious virions. Moreover, the initial antibody response captured acute HIV-1 virions without selection for different HIV-1 envelope sequences. In total, this study demonstrates that the composition of immune complexes are dynamic over the course of HIV-1 infection and are comprised initially of antibodies that nonselectively opsonize both infectious and noninfectious virions, likely contributing to the lack of efficacy of the antibody response during acute infection.

Background

Individuals diagnosed with HIV in developing countries are not always successfully linked to onward treatment services, resulting in missed opportunities for timely initiation of antiretroviral therapy, or prophylaxis for opportunistic infections. In collaboration with local stakeholders, we designed and assessed a referral system to link persons diagnosed at a voluntary counselling and testing (VCT) clinic in a rural district in northern Tanzania with a government-run HIV treatment clinic in a nearby city.

Methods

Two-part referral forms, with unique matching numbers on each side were implemented to facilitate access to the HIV clinic, and were subsequently reconciled to monitor the proportion of diagnosed clients who registered for these services, stratified by sex and referral period. Delays between referral and registration at the HIV clinic were calculated, and lists of non-attendees were generated to facilitate tracing among those who had given prior consent for follow up.

Transportation allowances and a "community escort" from a local home-based care organization were introduced for patients attending the HIV clinic, with supportive counselling services provided by the VCT counsellors and home-based care volunteers. Focus group discussions and in-depth interviews were conducted with health care workers and patients to assess the acceptability of the referral procedures.

Results

Referral uptake at the HIV clinic averaged 72% among men and 66% among women during the first three years of the national antiretroviral therapy (ART) programme, and gradually increased following the introduction of the transportation allowances and community escorts, but declined following a national VCT campaign. Most patients reported that the referral system facilitated their arrival at the HIV clinic, but expressed a desire for HIV treatment services to be in closer proximity to their homes. The referral forms proved to be an efficient and accepted method for assessing the effectiveness of the VCT clinic as an entry point for ART.

Conclusion

The referral system reduced delays in seeking care, and enabled the monitoring of access to HIV treatment among diagnosed persons. Similar systems to monitor referral uptake and linkages between HIV services could be readily implemented in other settings.

Introduction

There are limited data on acute HIV infection (AHI) prevalence during pregnancy.

Methods

Malawian pregnant women admitted in the third trimester and meeting eligibility criteria underwent dual HIV rapid antibody testing. AHI prevalence was retrospectively detected through HIV RNA pooling of seronegative plasma.

Results

Among 3825 pregnant women screened, dual HIV rapid testing indicated that 30.2% were HIV positive, 69.7% were HIV negative and 0.1% were indeterminate. Sensitivity and specificity of dual rapid testing was 99.0% and 98.7%, respectively. Of 2666 seronegative specimens, 2327 had samples available for HIV RNA pooling; 5 women (0.21%) (95% CI: 0.03, 0.40%) had AHI with a median peripartum viral load of 1,324,766 copies/mL.

Discussion

Pregnant women are at risk for AHI, warranting counseling of all women and their sexual partners about incident HIV during pregnancy. Dual HIV rapid tests have high sensitivity and specificity. HIV testing should be repeated in the third trimester and/or at delivery.

The earliest immune responses activated in acute human immunodeficiency virus type 1 infection (AHI) exert a critical influence on subsequent virus spread or containment. During this time frame, components of the innate immune system such as macrophages and DCs, NK cells, β-defensins, complement and other anti-microbial factors, which have all been implicated in modulating HIV infection, may play particularly important roles. A proteomics-based screen was performed on a cohort from whom samples were available at time points prior to the earliest positive HIV detection. The ability of selected factors found to be elevated in the plasma during AHI to inhibit HIV-1 replication was analyzed using in vitro PBMC and DC infection models. Analysis of unique plasma donor panels spanning the eclipse and viral expansion phases revealed very early alterations in plasma proteins in AHI. Induction of acute phase protein serum amyloid A (A-SAA) occurred as early as 5–7 days prior to the first detection of plasma viral RNA, considerably prior to any elevation in systemic cytokine levels. Furthermore, a proteolytic fragment of alpha–1-antitrypsin (AAT), termed virus inhibitory peptide (VIRIP), was observed in plasma coincident with viremia. Both A-SAA and VIRIP have anti-viral activity in vitro and quantitation of their plasma levels indicated that circulating concentrations are likely to be within the range of their inhibitory activity. Our results provide evidence for a first wave of host anti-viral defense occurring in the eclipse phase of AHI prior to systemic activation of other immune responses. Insights gained into the mechanism of action of acute-phase reactants and other innate molecules against HIV and how they are induced could be exploited for the future development of more efficient prophylactic vaccine strategies.

Author Summary

Acquired immune deficiency syndrome (AIDS) remains a major health problem worldwide, affecting predominantly the adult population in the western world and in developing countries in particular. Despite a tremendous effort to develop a cure or a vaccine that confers protection against human immunodeficiency virus (HIV-1) infection, this has not been achieved in a satisfactory manner to date. Recent research efforts have suggested that the earliest immune responses activated after exposure to the virus have an influence on virus spread, containment and disease progression. In this study, a panel of donors who provided plasma samples collected over a time-frame spanning the period before and immediately after detection of HIV-1 infection permitted an insight into the activation of the earliest systemic immune responses. We describe increases in plasma levels of acute-phase reactants and proteolytically processed fragments that have anti-viral activity in vitro. These inductions occur prior to detection of HIV-1 virus in the blood and before the first increases in systemic cytokine levels, which may represent the earliest systemic host antiviral response activated following infection.

Objectives

To investigate the adverse cardiac autonomic effects of sleep-disordered breathing (SDB) in a large population-based sample and a clinical sample of children.

Methods

Subjects were based a population-based sample of 700 and a clinically diagnosed sample of 43 SDB children. SDB was defined based on the Apnea Hyponea Index (AHI) hour over one night of polysomnography. Cardiac autonomic modulation was measured by heart rate variability (HRV) analysis of the beat-to-beat RR interval data collected during the polysomnography.

Results

The mean (SD) age was 112 (21) months, with 49% male and 25% non-white. 73.0% had AHI < 1 (No SDB), 25.8% had 1–5 AHI (Mild SDB), and 1.2% had ≥ 5 AHI (Moderate SDB). Among individuals with moderate SDB in the population-based sample and the clinically diagnosed SDB patients, the mean (SE) of HRV-high frequency power (HF) were significantly lower compared to children without SDB [6.00 (0.32) and 6.24 (0.14), respectively, vs. 6.68 (0.04) ms2, p < 0.05 and p < 0.01, respectively], whereas the low frequency power to high frequency power ratio (LF/HF) were significantly higher [1.62 (0.20) and 1.74 (0.09), respectively, vs. 0.99 (0.02), both p < 0.01)].

Conclusions

SDB in healthy young children and in clinical patients is significantly associated with impaired cardiac autonomic modulation, i.e., sympathetic overflow and weaker parasympathetic modulation, which may contribute to increased risk of acute cardiac events in persons with SDB, even before reaching the “high risk age.”

SUMMARY

OBJECTIVES

Voluntary counseling and testing (VCT) for the human immunodeficiency virus (HIV) is recommended for persons treated for tuberculosis (TB). Opportunities to diagnose HIV may be missed by limiting HIV testing to only persons diagnosed with TB. Among TB suspects in Uganda, we determined HIV prevalence, risk behaviors, and willingness to refer family for VCT.

METHODS

Consenting adult patients presenting for evaluation at a referral TB clinic received same-day VCT. TB diagnosis data were abstracted from clinical records.

RESULTS

Among 665 eligible patients, 565 (85%) consented to VCT. Among these, 238 (42%) were HIV-positive. Of the HIV-infected patients, 37% had received a non-TB diagnosis. HIV seroprevalence was higher in patients with a non-TB diagnosis (49%) than those diagnosed with TB (39%) (P = 0.02). Fewer than 6% of HIV-infected patients reported always using condoms with sexual partners. The majority of patients (86%) reported being ‘very willing’ to refer family members for VCT.

CONCLUSIONS

Over 35% of HIV-infected cases in our population would have been undetected if HIV testing was limited to cases with diagnosed TB. The high HIV seroprevalence in both TB and non-TB cases merits HIV testing for all patients evaluated at TB clinics. HIV-infected TB suspects reporting high-risk behavior are at risk for HIV transmission, and should receive risk-reduction counseling.

OBJECTIVES

To examine the association of sleep architecture, sleep disordered breathing, and cognition in older men.

DESIGN

A population-based cross-sectional study.

SETTING

6 sites in the United States.

PARTICIPANTS

2,909 community-dwelling men age 67 or older who were not selected on the basis of sleep problems or cognitive impairment.

MEASUREMENTS

Predictors were measured with in-home polysomnography: sleep architecture, nocturnal hypoxemia (any sleep time with SaO2<80%), apnea-hypopnea index (AHI), and arousal index. Cognitive outcomes were measured by the Modified Mini-Mental State Examination (3MS), Trails B test, and the Digit Vigilance Test (DVT).

RESULTS

Analyses adjusted by age, race, education, BMI, lifestyle, comorbidities and medication use show that those who spent less percent of time in rapid eye movement (REM) sleep had worse levels of cognition: compared to the highest quartile (≥23.7%), those in the lowest quartile (<14.8%) took an average of 5.9 seconds longer on the Trails B and 20.1 seconds longer on the DVT. Similarly, increased percent time spent in stage 1 sleep was related to poorer cognitive function. Those in the highest quartile of stage 1 sleep (≥8.6%) had worse cognitive scores on average compared to those in the lowest quartile (<4.0%). Those with nocturnal hypoxemia took longer to complete the DVT by an average of 22.3 seconds compared to those without, but no associations were found with 3MS or Trails B.

CONCLUSION

Spending less percent of time spent in REM sleep, more percent of time spent in stage 1 sleep, and having higher levels of nocturnal hypoxemia were associated with poorer cognition in older men. Further studies are needed to clarify the direction of these associations and to explore potential mechanisms.