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1.  Precision of the Kalon Herpes Simplex Virus Type 2 IgG ELISA: an international inter-laboratory assessment 
BMC Infectious Diseases  2015;15:398.
The commercial Kalon HSV-2 IgG ELISA is currently recommended for research use in sub-Saharan Africa because of its superior accuracy compared to other serologic assays. However, there are no data on key precision parameters of Kalon such as inter-operator variation, repeatability, and reproducibility, thus contributing to a barrier for its acceptance and use in clinical trials in sub-Saharan Africa. We evaluated the analytical and field precision of the Kalon HSV-2 IgG ELISA.
A total of 600 HIV-infected and uninfected serum samples from South Africa and Zambia, previously tested by the gold standard University of Washington HSV western blot (UW-WB), were tested using Kalon by two technologists in an United States reference laboratory. Aliquots of 183 samples were retested using Kalon by an on-site technologist in a South African laboratory and a Zambian laboratory.
Intra-assay variation was below 10 %. Intra-assay, intra-laboratory, and inter-laboratory correlation and agreement were significantly high (p < 0.01). In comparison to the UW-WB, accurate performance of Kalon was reproducible by each operator and laboratory. Receiver operating characteristic curve analysis indicated high selectivity of Kalon in the overall study population (area under the curve = 0.95, 95%CI = 0.92–0.97).
Kalon is a robust assay with high precision and reproducibility. Accordingly, operator errorlikely does not contribute to the variability observed in Kalon’s specificity throughout sera from sub-Saharan Africa.
In populations with optimal diagnostic accuracy, Kalon is a reliable stand-alone method for on-site HSV-2 IgG antibody detection.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-1130-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4591065  PMID: 26423888
Herpes; HSV-2; Kalon; Precision; Reproducibility; Accuracy; Sensitivity; Specificity; Zambia; South Africa
2.  HIV subtype is not associated with dementia among individuals with moderate and advanced immunosuppression in Kampala, Uganda 
Metabolic brain disease  2014;29(2):261-268.
HIV-associated neurocognitive disorders (HAND) are a common neurological manifestation of HIV infection. A previous study suggested that HIV dementia may be more common among patients with subtype D virus than among those with subtype A virus among HIV+ individuals with advanced immunosuppression. We conducted a study to evaluate the frequency of HIV dementia, and the association of HIV dementia with HIV subtype and compartmentalization among HIV+ individuals with moderate and advanced immunosuppression (CD4 lymphocyte count >150 cells/μL and < 250 cells/μL).
The study enrolled 117 antiretroviral naïve HIV+ individuals in Kampala, Uganda. HIV+ individuals received neurological, neuropsychological testing, and functional assessments, and gag and gp41 regions were subtyped. Subjects were considered infected with a specific subtype if both regions analyzed were from the same subtype.
41% of the HIV+ individuals had HIV dementia (mean CD4 lymphocyte count= 233 cells/μL). 67 individuals had subtype A, 25 individuals had subtype D, 24 individuals were classified as A/D recombinants, and one individual had subtype C. There was no difference in the frequency of HIV dementia when stratified by HIV subtype A and D and no association with compartmentalization between the cerebrospinal fluid and peripheral blood.
These results suggest that HIV dementia is common in HIV+ individuals in Uganda. There was no association between HIV subtype and dementia among HIV+ individuals with moderate and advanced immunosuppression. Future studies should be performed to confirm these results.
PMCID: PMC4024330  PMID: 24515303
HIV; dementia; subtype; Uganda; clade
4.  Incorrect Identification of Recent HIV Infection in Adults in the United States Using a Limiting-Antigen Avidity Assay 
AIDS (London, England)  2014;28(8):1227-1232.
To evaluate factors associated with misclassification by the limiting-antigen avidity (LAg-avidity) assay among individuals with long-standing HIV infection.
Samples were obtained from the Multicenter AIDS Cohort Study (MACS), and AIDS Linked to the IntraVenous Experience (ALIVE) cohort (1089 samples from 667 individuals, 595 samples collected 2–4 years and 494 samples collected 4–8 years after HIV seroconversion). Paired samples from both time points were available for 422 (63.3%) of the 667 individuals.
Samples were considered to be misclassified if the LAg-Avidity assay result was ≤1.5 normalized optical density (OD-n) units.
Overall, 4.8% (52/1089) of the samples were misclassified, including 1.8% (16/884, 95% confidence intervals [CI]: 1.09%–3.06%) of samples from individuals with viral loads >400 copies/mL and 1.4% (10/705) of samples from individuals with viral loads >400 copies/mL and CD4 cell counts >200 cells/μl (95% CI: 0.68%–2.60%). Age, race, gender, and mode of HIV acquisition were not associated with misclassification. In an adjusted analysis, viral load <400 copies/mL (adjusted odds ratio [aOR]: 3.72, 95% CI: 1.61–8.57), CD4 cell count <50 cells/μl (aOR: 5.41, 95% CI: 1.86–15.74), and low LAg-Avidity result (≤1.5 OD-n) from the earlier time point (aOR: 5.60, 95% CI: 1.55–20.25) were significantly associated with misclassification.
The manufacturer of the LAg-Avidity assay recommends excluding individuals from incidence surveys who are receiving antiretroviral therapy, are elite suppressors, or have AIDS (CD4 cell count <200 cells/μl). The results of this study indicate that those exclusions do not remove all sources of assay misclassification among individuals with long-standing HIV infection.
PMCID: PMC4102639  PMID: 24513567
LAg-Avidity; incidence; MSM; PWID; HIV; misclassification
5.  The Relationship between Alcohol Outlets, HIV Risk Behavior, and HSV-2 Infection among South African Young Women: A Cross-Sectional Study 
PLoS ONE  2015;10(5):e0125510.
Alcohol consumption has a disinhibiting effect that may make sexual risk behaviors and disease transmission more likely. The characteristics of alcohol-serving outlets (e.g. music, dim lights, lack of condoms) may further encourage risky sexual activity. We hypothesize that frequenting alcohol outlets will be associated with HIV risk.
In a sample of 2,533 school-attending young women in rural South Africa, we performed a cross-sectional analysis to examine the association between frequency of alcohol outlet visits in the last six months and four outcomes related to HIV risk: number of sex partners in the last three months, unprotected sex acts in the last three months, transactional sex with most recent partner, and HSV-2 infection. We also tested for interaction by alcohol consumption.
Visiting alcohol outlets was associated with having more sex partners [adjusted odds ratio (aOR), one versus zero partners (95% confidence interval (CI)): 1.51 (1.21, 1.88)], more unprotected sex acts [aOR, one versus zero acts (95% CI): 2.28 (1.52, 3.42)], higher levels of transactional sex [aOR (95% CI): 1.63 (1.03, 2.59)], and HSV-2 infection [aOR (95% CI): 1.30 (0.88, 1.91)]. In combination with exposure to alcohol consumption, visits to alcohol outlets were more strongly associated with all four outcomes than with either risk factor alone. Statistical evidence of interaction between alcohol outlet visits and alcohol consumption was observed for all outcomes except transactional sex.
Frequenting alcohol outlets was associated with increased sexual risk in rural South African young women, especially when they consumed alcohol. Sexual health interventions targeted at alcohol outlets may effectively reach adolescents at high risk for sexually transmitted infections like HIV and HSV-2.
Trial Registration
HIV Prevention Trials Network HPTN 068
PMCID: PMC4425652  PMID: 25954812
6.  HIV Shedding from Male Circumcision Wounds in HIV-Infected Men: A Prospective Cohort Study 
PLoS Medicine  2015;12(4):e1001820.
A randomized trial of voluntary medical male circumcision (MC) of HIV—infected men reported increased HIV transmission to female partners among men who resumed sexual intercourse prior to wound healing. We conducted a prospective observational study to assess penile HIV shedding after MC.
Methods and Findings
HIV shedding was evaluated among 223 HIV—infected men (183 self—reported not receiving antiretroviral therapy [ART], 11 self—reported receiving ART and had a detectable plasma viral load [VL], and 29 self—reported receiving ART and had an undetectable plasma VL [<400 copies/ml]) in Rakai, Uganda, between June 2009 and April 2012. Preoperative and weekly penile lavages collected for 6 wk and then at 12 wk were tested for HIV shedding and VL using a real—time quantitative PCR assay. Unadjusted prevalence risk ratios (PRRs) and adjusted PRRs (adjPRRs) of HIV shedding were estimated using modified Poisson regression with robust variance. HIV shedding was detected in 9.3% (17/183) of men not on ART prior to surgery and 39.3% (72/183) of these men during the entire study. Relative to baseline, the proportion shedding was significantly increased after MC at 1 wk (PRR = 1.87, 95% CI = 1.12–3.14, p = 0.012), 2 wk (PRR = 3.16, 95% CI = 1.94–5.13, p < 0.001), and 3 wk (PRR = 1.98, 95% CI = 1.19–3.28, p = 0.008) after MC. However, compared to baseline, HIV shedding was decreased by 6 wk after MC (PRR = 0.27, 95% CI = 0.09–0.83, p = 0.023) and remained suppressed at 12 wk after MC (PRR = 0.19, 95% CI = 0.06–0.64, p = 0.008). Detectable HIV shedding from MC wounds occurred in more study visits among men with an HIV plasma VL > 50,000 copies/ml than among those with an HIV plasma VL < 400 copies/ml (adjPRR = 10.3, 95% CI = 4.25–24.90, p < 0.001). Detectable HIV shedding was less common in visits from men with healed MC wounds compared to visits from men without healed wounds (adjPRR = 0.12, 95% CI = 0.07–0.23, p < 0.001) and in visits from men on ART with undetectable plasma VL compared to men not on ART (PRR = 0.15, 95% CI = 0.05–0.43, p = 0.001). Among men with detectable penile HIV shedding, the median log10 HIV copies/milliliter of lavage fluid was significantly lower in men with ART—induced undetectable plasma VL (1.93, interquartile range [IQR] = 1.83–2.14) than in men not on ART (2.63, IQR = 2.28–3.22, p < 0.001). Limitations of this observational study include significant differences in baseline covariates, lack of confirmed receipt of ART for individuals who reported ART use, and lack of information on potential ART initiation during follow—up for those who were not on ART at enrollment.
Penile HIV shedding is significantly reduced after healing of MC wounds. Lower plasma VL is associated with decreased frequency and quantity of HIV shedding from MC wounds. Starting ART prior to MC should be considered to reduce male-to-female HIV transmission risk. Research is needed to assess the time on ART required to decrease shedding, and the acceptability and feasibility of initiating ART at the time of MC.
In this prospective cohort study, Aaron Tobian and colleagues examine the associations between male circumcision wound healing, as well as plasma viral load, and HIV shedding from male circumcision wounds.
Editors' Summary
About 35 million people are currently infected with HIV, the virus that causes AIDS by destroying immune system cells, and every year, 2 million more people become HIV-positive. Antiretroviral therapy (ART) can keep HIV in check, but there is no cure for AIDS. Consequently, prevention of HIV acquisition and transmission is an important component of efforts to control the AIDS epidemic. Because HIV is most often spread through unprotected sex with an infected partner, individuals can reduce their risk of becoming HIV-positive by abstaining from sex, by having only one or a few partners, and by using male or female condoms. In addition, three trials undertaken in sub-Saharan Africa a decade ago showed that male circumcision—the surgical removal of the foreskin, a loose fold of skin that covers the head of the penis—can halve the HIV acquisition rate in men. Thus, since 2007, the World Health Organization (WHO) has recommended voluntary medical male circumcision for individuals living in countries with high HIV prevalence as part of its HIV prevention strategy.
Why Was This Study Done?
With the rollout of voluntary medical male circumcision programs, circumcision has become more normative (regarded as acceptable), and HIV-positive men are increasingly requesting circumcision because they want to avoid any stigma associated with being uncircumcised and because circumcision provides health benefits. WHO recommends that, although circumcision should not be promoted for HIV-positive men, voluntary circumcision programs should operate on HIV-positive men if they request circumcision. However, in a trial of circumcision of HIV-infected men, HIV transmission to their female partners increased if the couples had sexual intercourse before the circumcision wound had healed. Moreover, in studies of current male circumcision programs, two-thirds of married men and a third of all men reported that they resumed sexual intercourse before their circumcision wounds had healed. Thus, better understanding of how male circumcision increases HIV transmission to female partners is essential, and improved ways to prevent transmission in the post-surgical period are needed. Here, in a prospective observational study (an investigation that collects data over time from people undergoing a specific procedure), the researchers assess HIV shedding from the penis after circumcision.
What Did the Researchers Do and Find?
The researchers evaluated penile HIV shedding among 223 HIV-infected men (183 men who self-reported not being on ART and 40 men who self-reported being on ART, 29 of whom had no detectable virus in their blood) living in Rakai, Uganda, by examining preoperative and postoperative penile lavage (wash) samples. Viral shedding was detected in 9.3% of the men not on ART before surgery and in 39.3% of these men during the entire study. Relative to baseline, a greater proportion of men shed virus at one, two, and three weeks after circumcision, but a lower proportion shed virus at six and twelve weeks after circumcision. HIV shedding was more frequent among men with a high amount of virus in their blood (a high viral load) than among men with a low viral load. Moreover, the frequency of HIV shedding was lower in visits from men with healed circumcision wounds than in visits from men with unhealed wounds, and in visits from men on ART with no detectable virus in their blood than in visits from men not on ART men. Finally, among men with detectable penile HIV shedding, men on ART with no detectable virus in their blood shed fewer copies of virus than men not on ART.
What Do These Findings Mean?
The findings suggest that healed circumcision wounds are associated with reduced penile HIV shedding in HIV-positive men compared to unhealed circumcision wounds and HIV shedding prior to circumcision In addition, they suggest that a lower HIV viral load in the blood is associated with a decreased frequency and quantity of HIV shedding from circumcision wounds. Because this was an observational study, these findings cannot prove that healed wounds or reduced blood viral load actually caused reduced penile HIV shedding. Moreover, the accuracy of these findings may be affected by the lack of information on ART initiation during follow-up among men not initially on ART and by reliance on ART self-report. Nevertheless, these findings highlight the importance of counseling HIV-positive men undergoing circumcision to avoid sexual intercourse until their circumcision wound heals. In addition, these findings suggest that it might be possible to reduce HIV transmission among HIV-positive men immediately after circumcision by starting these individuals on ART before circumcision. Further research is needed to assess how long before circumcision ART should be initiated and to assess the acceptability and feasibility of initiating ART concurrent with circumcision.
Additional Information
Please access these websites via the online version of this summary at
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, information on male circumcision for the prevention of HIV transmission, and personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV prevention, on voluntary medical male circumcision for HIV prevention, and on HIV/AIDS in sub-Saharan Africa; Avert also provides personal stories about living with HIV/AIDS
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including on voluntary medical male circumcision for HIV prevention
The UNAIDS Fast-Track Strategy to End the AIDS Epidemic by 2030 provides up-to-date information about the AIDS epidemic and efforts to halt it
The Clearinghouse on Male Circumcision for HIV Prevention provides up-to-date information and resources on male circumcision for HIV prevention
PMCID: PMC4412625  PMID: 25919012
7.  Immune Responses in Ugandan Women Infected with Subtype A and D HIV Using the BED Capture Immunoassay and an Antibody Avidity Assay 
Analysis of samples from Uganda using serologic HIV incidence assays reveal that individuals with subtype D infection often have weak humoral immune responses to HIV infection. It is unclear whether this reflects a poor initial response to infection or a waning antibody response later in infection.
Materials and Methods:
Samples (N=2614) were obtained from 114 women aged 18-45 in the Ugandan GS Study cohort (2001-2009; 82 subtype A, 32 subtype D; median 23 samples/women, range 3-41 samples, median follow-up of 6.6 years). Samples were analyzed using the BED capture immunoassay (cutoff 0.8 OD-n) and the avidity assay (cutoff 90% AI). Antibody maturation was assessed by having the BED-CEIA or avidity value exceed the assay cutoff 1 or 2 years after infection. A waning antibody response was measured by having the BED-CEIA or avidity value fall >20% below the maximum value.
For the BED-CEIA, eight women with subtype A infection and three women with subtype D infection never progressed past the cutoff value (median 5.9 years follow-up after infection). Six women with subtype D infection never achieved an AI >90%. Subtype did not impact the proportion of women whose assay values regressed by >20% of the maximal value (for BED-CEIA: 33% for A, 41% for D, p=0.51; for avidity: 1% for A, 6% for D, p=0.19).
The higher frequency of misclassification of individuals with long-term subtype D infection as recently infected using serologic incidence assays reflects a weak initial antibody response to HIV infection that is sustained over time.
PMCID: PMC3942792  PMID: 24583613
subtype; incidence; BED-CEIA; avidity; immune response; Uganda
8.  Impact of HIV Subtype on Performance of the Limiting Antigen-Avidity Enzyme Immunoassay, the Bio-Rad Avidity Assay, and the BED Capture Immunoassay in Rakai, Uganda 
Previous studies demonstrated that individuals with subtype D HIV infection who had been infected for 2 or more years were frequently misclassified as assay positive using cross-sectional incidence assays. Samples from 510 subjects (212 subtype A, 298 subtype D) who were infected for 2.2 to 14.5 years (median 5.4 years) and were not virally suppressed were tested using an LAg-Avidity enzyme immunoassay (LAg-Avidity EIA), Bio-Rad Avidity assay, and BED capture enzyme immunoassay (BED-CEIA). The performance of these three assays was evaluated using various assay cutoff values [LAg-Avidity EIA: <1.0 OD-n and <2.0 OD-n; Bio-Rad Avidity assay: <40% avidity index (AI) and <80% AI; BED-CEIA: <0.8 OD-n]. The mean LAg-Avidity EIA result was higher for subtype A than D (4.54±0.95 vs. 3.86±1.26, p<0.001); the mean Bio-Rad Avidity assay result was higher for subtype A than D (88.9%±12.5% vs. 75.1±30.5, p<0.001); and the mean BED-CEIA result was similar for the two subtypes (2.2±1.2 OD-n for subtype A, 2.2±1.3 OD-n for subtype D, p<0.9). The frequency of misclassification was higher for individuals with subtype D infection compared to those with subtype A infection, using either the LAg-Avidity EIA with a cutoff of <2.0 OD-n or the Bio-Rad Avidity assay with cutoffs of <40% or <80% AI. No subtype-specific differences in assay performance were observed using the BED-CEIA. Sex and age were not significantly associated with misclassification by any assay. The LAg-Avidity EIA with a cutoff <1.0 OD-n had the lowest frequency of misclassification in this Ugandan population.
PMCID: PMC3976571  PMID: 24083837
9.  Failure to Identify HIV-Infected Individuals in a Clinical Trial Using a Single HIV Rapid Test for Screening 
HIV clinical trials  2014;15(2):62-68.
In the HIV Prevention Trials Network (HPTN) 061 study, 8 (2.3%) of 348 HIV-infected participants identified as HIV uninfected at study enrollment using a single HIV rapid test for screening were found to be HIV infected after additional testing.
To evaluate the performance of different HIV assays for detection of HIV infection in HPTN 061 participants with missed infection and individuals with viral suppression.
Plasma samples from 8 HPTN 061 participants, 17 elite controllers, and 101 individuals on antiretroviral treatment (ART) were tested for HIV with 3 rapid tests, 2 laboratory-based immunoassays, and a Western blot assay. The HPTN 061 samples were also tested with 2 HIV RNA assays and an antiretroviral drug assay.
Of the 8 HPTN 061 participants with missed infection, 1 was an elite controller, 1 was taking ART, 2 were missed because of testing or clerical errors, 1 had recent HIV infection (identified using a multi-assay algorithm), and 3 had acute HIV infection. Two (1.7%) of 118 individuals with viral suppression (both taking ART) had at least 1 false-negative test.
In clinical trials, HIV infections can be missed for a variety of reasons. Using more than one assay to screen for HIV infection may reduce the number of missed infections.
PMCID: PMC4167641  PMID: 24710920
antiretroviral therapy; elite controller; HIV; rapid test; viral suppression
10.  HIV Type 1 Polymerase Gene Polymorphisms Are Associated With Phenotypic Differences in Replication Capacity and Disease Progression 
Background. Determinants of intersubtype differences in human immunodeficiency virus type 1 (HIV-1) clinical disease progression remain unknown.
Methods. HIV-1 subtype was independently determined for 5 separate genomic regions in 396 HIV-1 seroconverters from Rakai, Uganda, using a multiregion hybridization assay. Replication capacities (RC) in samples from a subset of 145 of these subjects were determined. HIV-1 genomic regions and pol RC were examined for association with disease progression. Amino acid polymorphisms were examined for association with pol RC.
Results. In multivariate analyses, the hazard for progression to the composite end point (defined as a CD4+ T-cell count <250 cells/mm3, antiretroviral therapy initiation, or death) among patients with subtype D pol infection was 2.4 times the hazard for those infected with subtype A pol infection (P = .001). Compared with subtype A pol (the reference group), the hazard for progression to the composite end point for subtype D pol infection with a pol RC >67% (ie, the median pol RC) was significantly greater (HR, 4.6; 95% confidence interval [CI], 1.9–11.0; P = .001), whereas the hazard for progression to the composite end point for subtype D pol infection with a pol RC ≤67% was not significantly different (HR, 2.2; 95% CI, 1.0–4.9; P = .051). Amino acid substitutions at protease positions 62 and 64 and at reverse transcriptase position 272 were associated with significant differences in pol RC.
Conclusions. HIV-1 pol gene intersubtype and RC differences are associated with disease progression and may be influenced by amino acid polymorphisms.
PMCID: PMC3864385  PMID: 23922373
HIV-1 Subtype; subtype A; subtype D; disease progression; polymerase; replication capacity; amino acid polymorphisms
11.  High Frequency of False-Positive Hepatitis C Virus Enzyme-Linked Immunosorbent Assay in Rakai, Uganda 
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.
PMCID: PMC3840403  PMID: 24051866
hepatitis C virus; ELISA; Africa
12.  Characterization of HIV-1 envelopes in acutely and chronically infected injection drug users 
Retrovirology  2014;11:106.
Mucosally acquired human immunodeficiency virus type 1 (HIV-1) infection results from a limited number of variants, and these infecting strains potentially have unique properties, such as increased susceptibility to entry blockers, relative interferon-alpha (IFN-α) resistance, and replication differences in some primary cells. There is no data about the phenotypic properties of HIV-1 envelope variants found early after acquisition among subjects infected through injection drug use (IDU). For the first time, we compared the characteristics of virus envelopes among injection drug users sampled prior to seroconversion (HIV RNA+/Ab-), within 1 year (early), and more than 2 years (chronic) after estimated acquisition.
Virus envelopes from 7 HIV RNA+/Ab- subjects possessed lower genetic diversity and divergence compared to 7 unrelated individuals sampled during the chronic phase of disease. Replication competent recombinant viruses incorporating the HIV RNA+/Ab- as compared to the chronic phase envelopes were significantly more sensitive to a CCR5 receptor inhibitor and IFN-α and showed a statistical trend toward greater sensitivity to a fusion blocker. The early as compared to chronic infection envelopes also demonstrated a statistical trend or significantly greater sensitivity to CCR5 and fusion inhibitor and IFN- α. The HIV RNA+/Ab- as compared to chronic envelope viruses replicated to a lower extent in mature monocyte derived dendritic cells – CD4+ T cell co-cultures, but there were no significant replication differences in other primary cells among the viruses with envelopes from the 3 different stages of infection.
Similar to mucosal acquisition, HIV-1 envelope quasispecies present in injection drug users prior to seroconversion have unique phenotypic properties compared to those circulating during the chronic phase of disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s12977-014-0106-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4253609  PMID: 25430652
HIV-1; Envelope; Transmission; Receptor; Replication; Injection drug use; Dendritic cells; Selection; Interferon
13.  Effect of community-based voluntary counselling and testing on HIV incidence and social and behavioural outcomes (NIMH Project Accept; HPTN 043): a cluster-randomised trial 
The lancet global health  2014;2(5):e267-e277.
NIMH Project Accept (HPTN 043) was a cluster-randomized trial that tested whether a multicomponent, multi-level prevention strategy (community-based voluntary counselling and testing [CBVCT]) reduced HIV incidence compared to standard voluntary counselling and testing (SVCT).
Forty-eight communities were enrolled at five sites in South Africa, Tanzania, Zimbabwe, and Thailand. CBVCT was designed to make testing more accessible in communities, engage communities through outreach, and provide post-test support services. SVCT comprised standard VCT services established at existing facilities. Communities were randomized in matched pairs to 36 months of CBVCT or SVCT. Data were collected at baseline (n=14,567) and post-intervention (n=56,683) by cross-sectional random surveys of 18–32 year-old community residents. HIV incidence was estimated using a cross-sectional multi-assay algorithm. Thailand was excluded from incidence analyses due to low HIV prevalence.
The estimated incidence in the CBVCT was 1.52% vs. 1.81% in the SVCT with an estimated reduction in HIV incidence of 13·9% (relative risk [RR]=0·86; 95% confidence interval [CI]=0·725–1·023; p=0·08). Women older than 24 years had RR=0·70 (95% CI=0·54–0·90; p=0·009). CBVCT increased testing rates by 25% overall (95% CI=12%–39%; p=0·0003), by 45% among men and 15% among women. No overall effect on sexual risk behaviour was observed. However, among HIV-infected participants, CBVCT reduced the number of sexual partners by 8% (95% CI=1%–15%; p=0.03) and the proportion of multiple partnerships by 30% (95% CI=8%-46%; p=0.01). Social norms regarding HIV testing were improved in CBVCT communities.
The intervention was effective in increasing HIV testing, particularly among men, promoted positive social norms regarding testing, and reduced behavioural risk among HIV-infected participants. A modest reduction in HIV incidence was observed. This intervention focused primarily on HIV detection. Current and future studies that include strategies for HIV treatment and viral suppression should demonstrate further incidence reductions.
PMCID: PMC4131207  PMID: 25103167
HIV; incidence; Project Accept; Africa; HPTN 043
14.  Differential Specificity of HIV Incidence Assays in HIV Subtypes A and D-Infected Individuals from Rakai, Uganda 
AIDS Research and Human Retroviruses  2013;29(8):1146-1150.
Assays to determine HIV incidence from cross-sectional surveys have exhibited a high rate of false-recent misclassification in Kenya and Uganda where HIV subtypes A and D predominate. Samples from individuals infected with HIV for at least 2 years with known infecting subtype (133 subtype A, 373 subtype D) were tested using the BED-CEIA and an avidity assay. Both assays had a higher rate of false-recent misclassification for subtype D compared to subtype A (13.7% vs. 6.0%, p=0.02 for BED-CEIA; 11.0% vs. 1.5%, p<0.001 for avidity). For subtype D samples, false-recent misclassification by the BED-CEIA was also more frequent in women than men (15.0% vs. 5.6%, p=0.002), and for samples where that had an amino acid other than lysine at position 12 in the BED-CEIA peptide coding region (p=0.002). Furthermore in subtype D-infected individuals, samples misclassified by one assay were 3.5 times more likely to be misclassified by the other assay. Differential misclassification by infecting subtype of long-term infected individuals as recently infected makes it difficult to use these assays individually to estimate population level incidence without precise knowledge of the distribution of these subtypes within populations where subtype A and D cocirculate. The association of misclassification of the BED-CEIA with the avidity assay in subtype D-infected individuals limits the utility of using these assays in combination within this population.
PMCID: PMC3715796  PMID: 23641870
15.  Prevalence and Factors Associated with Herpes Simplex Virus Type 2 Infection in Patients Attending a Baltimore City Emergency Department 
PLoS ONE  2014;9(7):e102422.
Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted disease, but there is limited data on its epidemiology among urban populations. The urban Emergency Department (ED) is a potential venue for surveillance as it predominantly serves an inner city minority population. We evaluate the seroprevalence and factors associated with HSV-2 infection among patients attending the Johns Hopkins Hospital Adult Emergency Department (JHH ED).
An identity unlinked-serosurvey was conducted between 6/2007 and 9/2007 in the JHH ED; sera were tested by the Focus HerpeSelect ELISA. Prevalence risk ratios (PRR) were used to determine factors associated with HSV-2 infection.
Of 3,408 serum samples, 1,853 (54.4%) were seropositive for HSV-2. Females (adjPRR  = 1.47, 95% CI 1.38–1.56), non-Hispanic blacks (adjPRR  = 2.03, 95% CI 1.82–2.27), single (adjPRR  = 1.15, 95% CI 1.07–1.25), divorced (adjPRR  = 1.28, 95% CI 1.15–1.41), and unemployed patients (adjPRR  = 1.13, 95% CI 1.05–1.21) had significantly higher rates of HSV-2 infection. Though certain zip codes had significantly higher seroprevalence of HSV-2, this effect was completely attenuated when controlling for age and gender.
Seroprevalence of HSV-2 in the JHH ED was higher than U.S. national estimates; however, factors associated with HSV-2 infection were similar. The high seroprevalence of HSV-2 in this urban ED highlights the need for targeted testing and treatment. Cross-sectional serosurveys in the urban ED may help to examine the epidemiology of HSV-2.
PMCID: PMC4103852  PMID: 25036862
16.  Differential loss of invariant NKT cells and FoxP3+ regulatory T cells in HIV-1 subtype A and subtype D infections 
HIV-1 subtype D is associated with faster disease progression as compared to subtype A. Immunological correlates of this difference remain undefined. We investigated invariant natural killer T cells and FoxP3+ regulatory T cells in Ugandans infected with either subtype. Loss of iNKT cells was pronounced in subtype D, whereas Tregs displayed more profound loss in subtype A infection. iNKT cell levels were associated with CD4 T cell IL-2 production in subtype A, but not D, infection. Thus, these viral subtypes are associated with differential loss of iNKT cells and Tregs that may influence the quality of the adaptive immune response.
PMCID: PMC3683089  PMID: 23403863
HIV-1; viral subtype; AIDS; iNKT cell; CD1d; T regulatory cell
17.  Cross-Sectional HIV Incidence Estimation in HIV Prevention Research 
Accurate methods for estimating HIV incidence from cross-sectional samples would have great utility in prevention research. This report describes recent improvements in cross-sectional methods that significantly improve their accuracy. These improvements are based on the use of multiple biomarkers to identify recent HIV infections. These multi-assay algorithms (MAAs) use assays in a hierarchical approach for testing that minimizes the effort and cost of incidence estimation. These MAAs do not require mathematical adjustments for accurate estimation of the incidence rates in study populations in the year prior to sample collection. MAAs provide a practical, accurate, and cost-effective approach for cross-sectional HIV incidence estimation that can be used for HIV prevention research and global epidemic monitoring.
PMCID: PMC3737594  PMID: 23764641
HIV; incidence; cross-sectional; multi-assay algorithm
18.  HIV Diversity as a Biomarker for HIV Incidence Estimation: Including a High-Resolution Melting Diversity Assay in a Multiassay Algorithm 
Journal of Clinical Microbiology  2014;52(1):115-121.
Multiassay algorithms (MAAs) can be used to estimate cross-sectional HIV incidence. We previously identified a robust MAA that includes the BED capture enzyme immunoassay (BED-CEIA), the Bio-Rad Avidity assay, viral load, and CD4 cell count. In this report, we evaluated MAAs that include a high-resolution melting (HRM) diversity assay that does not require sequencing. HRM scores were determined for eight regions of the HIV genome (2 in gag, 1 in pol, and 5 in env). The MAAs that were evaluated included the BED-CEIA, the Bio-Rad Avidity assay, viral load, and the HRM diversity assay, using HRM scores from different regions and a range of region-specific HRM diversity assay cutoffs. The performance characteristics based on the proportion of samples that were classified as MAA positive by duration of infection were determined for each MAA, including the mean window period. The cross-sectional incidence estimates obtained using optimized MAAs were compared to longitudinal incidence estimates for three cohorts in the United States. The performance of the HRM-based MAA was nearly identical to that of the MAA that included CD4 cell count. The HRM-based MAA had a mean window period of 154 days and provided cross-sectional incidence estimates that were similar to those based on cohort follow-up. HIV diversity is a useful biomarker for estimating HIV incidence. MAAs that include the HRM diversity assay can provide accurate HIV incidence estimates using stored blood plasma or serum samples without a requirement for CD4 cell count data.
PMCID: PMC3911463  PMID: 24153134
19.  A Comparison of Two Measures of HIV Diversity in Multi-Assay Algorithms for HIV Incidence Estimation 
PLoS ONE  2014;9(6):e101043.
Multi-assay algorithms (MAAs) can be used to estimate HIV incidence in cross-sectional surveys. We compared the performance of two MAAs that use HIV diversity as one of four biomarkers for analysis of HIV incidence.
Both MAAs included two serologic assays (LAg-Avidity assay and BioRad-Avidity assay), HIV viral load, and an HIV diversity assay. HIV diversity was quantified using either a high resolution melting (HRM) diversity assay that does not require HIV sequencing (HRM score for a 239 base pair env region) or sequence ambiguity (the percentage of ambiguous bases in a 1,302 base pair pol region). Samples were classified as MAA positive (likely from individuals with recent HIV infection) if they met the criteria for all of the assays in the MAA. The following performance characteristics were assessed: (1) the proportion of samples classified as MAA positive as a function of duration of infection, (2) the mean window period, (3) the shadow (the time period before sample collection that is being assessed by the MAA), and (4) the accuracy of cross-sectional incidence estimates for three cohort studies.
The proportion of samples classified as MAA positive as a function of duration of infection was nearly identical for the two MAAs. The mean window period was 141 days for the HRM-based MAA and 131 days for the sequence ambiguity-based MAA. The shadows for both MAAs were <1 year. Both MAAs provided cross-sectional HIV incidence estimates that were very similar to longitudinal incidence estimates based on HIV seroconversion.
MAAs that include the LAg-Avidity assay, the BioRad-Avidity assay, HIV viral load, and HIV diversity can provide accurate HIV incidence estimates. Sequence ambiguity measures obtained using a commercially-available HIV genotyping system can be used as an alternative to HRM scores in MAAs for cross-sectional HIV incidence estimation.
PMCID: PMC4072769  PMID: 24968135
20.  Herpes Simplex Virus Type 2 Infection among Commercial Sex Workers in Kunming, Yunnan Province, China 
International journal of STD & AIDS  2008;19(10):694-697.
A cross-sectional prevalence survey was conducted to determine the sociodemographic correlates of HSV-2 infection among commercial sex workers (CSWs) in Kunming, Yunnan Province of China. HSV-2 prevalence was 33.0%, HIV infection was 2.4%, and HCV infections was 6.8%. Subjects who were positive for HSV-2 had a significantly higher prevalence of HIV infection (5.5% vs. 0.9%, p=0.002; OR: 6.4, p=0.006) and HCV infection (18.7% vs. 2.4%, p<0.001; OR: 7.6, p<0.001) compared to HSV-2 negative individuals. Risk factors that increased the odds of HSV-2 infection were HIV infection, HCV infection, being female, and having a steady sex partner within the last six months (p≤0.01). In a multivariate analysis, female sex workers (OR: 6.6, p<0.001), HCV infection (OR: 5.9, p<0.001), and having a sex partner within the last 6 months (OR: 2.2, p<0.05) had greater odds of being infected with HSV-2. A strong relationship was found between HSV-2, HIV, and HCV infections.
PMCID: PMC3991299  PMID: 18824623
commercial sex workers (CSWs); herpes simplex virus type 2 (HSV-2); human immunodeficiency virus (HIV); hepatitis C virus (HCV); China
21.  The Role of Viral Introductions in Sustaining Community-Based HIV Epidemics in Rural Uganda: Evidence from Spatial Clustering, Phylogenetics, and Egocentric Transmission Models 
PLoS Medicine  2014;11(3):e1001610.
Using different approaches to investigate HIV transmission patterns, Justin Lessler and colleagues find that extra-community HIV introductions are frequent and likely play a role in sustaining the epidemic in the Rakai community.
Please see later in the article for the Editors' Summary
It is often assumed that local sexual networks play a dominant role in HIV spread in sub-Saharan Africa. The aim of this study was to determine the extent to which continued HIV transmission in rural communities—home to two-thirds of the African population—is driven by intra-community sexual networks versus viral introductions from outside of communities.
Methods and Findings
We analyzed the spatial dynamics of HIV transmission in rural Rakai District, Uganda, using data from a cohort of 14,594 individuals within 46 communities. We applied spatial clustering statistics, viral phylogenetics, and probabilistic transmission models to quantify the relative contribution of viral introductions into communities versus community- and household-based transmission to HIV incidence. Individuals living in households with HIV-incident (n = 189) or HIV-prevalent (n = 1,597) persons were 3.2 (95% CI: 2.7–3.7) times more likely to be HIV infected themselves compared to the population in general, but spatial clustering outside of households was relatively weak and was confined to distances <500 m. Phylogenetic analyses of gag and env genes suggest that chains of transmission frequently cross community boundaries. A total of 95 phylogenetic clusters were identified, of which 44% (42/95) were two individuals sharing a household. Among the remaining clusters, 72% (38/53) crossed community boundaries. Using the locations of self-reported sexual partners, we estimate that 39% (95% CI: 34%–42%) of new viral transmissions occur within stable household partnerships, and that among those infected by extra-household sexual partners, 62% (95% CI: 55%–70%) are infected by sexual partners from outside their community. These results rely on the representativeness of the sample and the quality of self-reported partnership data and may not reflect HIV transmission patterns outside of Rakai.
Our findings suggest that HIV introductions into communities are common and account for a significant proportion of new HIV infections acquired outside of households in rural Uganda, though the extent to which this is true elsewhere in Africa remains unknown. Our results also suggest that HIV prevention efforts should be implemented at spatial scales broader than the community and should target key populations likely responsible for introductions into communities.
Please see later in the article for the Editors' Summary
Editors' Summary
About 35 million people (25 million of whom live in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS, and about 2.3 million people become newly infected every year. HIV destroys immune system cells, leaving infected individuals susceptible to other infections. HIV infection can be controlled by taking antiretroviral drugs (antiretroviral therapy, or ART) daily throughout life. Although originally available only to people living in wealthy countries, recent political efforts mean that 9.7 million people in low- and middle-income countries now have access to ART. However, ART does not cure HIV infection, so prevention of viral transmission remains extremely important. Because HIV is usually transmitted through unprotected sex with an infected partner, individuals can reduce their risk of infection by abstaining from sex, by having one or a few partners, and by using condoms. Male circumcision also reduces HIV transmission. In addition to reducing illness and death among HIV-positive people, ART also reduces HIV transmission.
Why Was This Study Done?
Effective HIV control requires an understanding of how HIV spreads through sexual networks. These networks include sexual partnerships between individuals in households, between community members in different households, and between individuals from different communities. Local sexual networks (household and intra-community sexual partnerships) are sometimes assumed to be the dominant driving force in HIV spread in sub-Saharan Africa, but are viral introductions from sexual partnerships with individuals outside the community also important? This question needs answering because the effectiveness of interventions such as ART as prevention partly depends on how many new infections in an intervention area are attributable to infection from partners residing in that area and how many are attributable to infection from partners living elsewhere. Here, the researchers use three analytical methods—spatial clustering statistics, viral phylogenetics, and egocentric transmission modeling—to ask whether HIV transmission in rural Uganda is driven predominantly by intra-community sexual networks. Spatial clustering analysis uses the geographical coordinates of households to measure the tendency of HIV-infected people to cluster spatially at scales consistent with community transmission. Viral phylogenetic analysis examines the genetic relatedness of viruses; if transmission is through local networks, viruses in newly infected individuals should more closely resemble viruses in other community members than those in people outside the community. Egocentric transmission modelling uses information on the locations of recent sexual partners to estimate the proportions of new transmissions from household, intra-community, and extra-community partners.
What Did the Researchers Do and Find?
The researchers applied their three analytical methods to data collected from 14,594 individuals living in 46 communities (governmental administrative units) in Rakai District, Uganda. Spatial clustering analysis indicated that individuals who lived in households with individuals with incident HIV (newly diagnosed) or prevalent HIV (previously diagnosed) were 3.2 times more likely than the general population to be HIV-positive themselves. Spatial clustering outside households was relatively weak, however, and was confined to distances of less than half a kilometer. Viral phylogenetic analysis indicated that 44% of phylogenetic clusters (viruses with related genetic sequences found in more than one individual) were within households, but that 40% of clusters crossed community borders. Finally, analysis of the locations of self-reported sexual partners indicated that 39% of new viral transmissions occurred within stable household partnerships, but that among people newly infected by extra-household partners, nearly two-thirds were infected by partners from outside their community.
What Do These Findings Mean?
The results of all three analyses suggest that HIV introductions into communities are frequent and are likely to play an important role in sustaining HIV transmission in the Rakai District. Specifically, within this rural HIV-endemic region (a region where HIV infection is always present), viral introductions combined with intra-household transmission account for the majority of new infections, although community-based sexual networks also play a critical role in HIV transmission. These findings may not be generalizable to the broader Ugandan population or to other regions of Africa, and their accuracy is likely to be limited by the use of self-reported sexual partner data. Nevertheless, these findings indicate that the dynamics of HIV transmission in rural Uganda (and probably elsewhere) are complex. Consequently, to halt the spread of HIV, prevention efforts will need to be implemented at spatial scales broader than individual communities, and key populations that are likely to introduce HIV into communities will need to be targeted.
Additional Information
Please access these websites via the online version of this summary at
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Uganda and on HIV prevention strategies (in English and Spanish)
The UNAIDS Report on the Global AIDS Epidemic 2013 provides up-to-date information about the AIDS epidemic and efforts to halt it
The Center for AIDS Prevention Studies (University of California, San Francisco) has a fact sheet about sexual networks and HIV prevention
Wikipedia provides information on spatial clustering analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
A PLOS Computational Biology Topic Page (a review article that is a published copy of record of a dynamic version of the article as found in Wikipedia) about viral phylodynamics is available
Personal stories about living with HIV/AIDS are available through Avert, NAM/aidsmap, and Healthtalkonline
PMCID: PMC3942316  PMID: 24595023
23.  Estimation of HIV Incidence Using Multiple Biomarkers 
American Journal of Epidemiology  2013;177(3):264-272.
The incidence of human immunodeficiency virus (HIV) is the rate at which new HIV infections occur in populations. The development of accurate, practical, and cost-effective approaches to estimation of HIV incidence is a priority among researchers in HIV surveillance because of limitations with existing methods. In this paper, we develop methods for estimating HIV incidence rates using multiple biomarkers in biological samples collected from a cross-sectional survey. An advantage of the method is that it does not require longitudinal follow-up of individuals. We use assays for BED, avidity, viral load, and CD4 cell count data from clade B samples collected in several US epidemiologic cohorts between 1987 and 2010. Considering issues of accuracy, cost, and implementation, we identify optimal multiassay algorithms for estimating incidence. We find that the multiple-biomarker approach to cross-sectional HIV incidence estimation corrects the significant deficiencies of currently available approaches and is a potentially powerful and practical tool for HIV surveillance.
PMCID: PMC3626051  PMID: 23302151
acquired immunodeficiency syndrome; algorithms; cross-sectional studies; HIV; incidence; models, statistical
24.  Use of a Multifaceted Approach to Analyze HIV Incidence in a Cohort Study of Women in the United States: HIV Prevention Trials Network 064 Study 
The Journal of Infectious Diseases  2012;207(2):223-231.
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.
Clinical Trials Registration. NCT00995176.
PMCID: PMC3532822  PMID: 23129758
HIV-1; women; United States; incidence
25.  HIV Incidence Determination in the United States: A Multiassay Approach 
The Journal of Infectious Diseases  2012;207(2):232-239.
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 BED-CEIA 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, .51%–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.
PMCID: PMC3532826  PMID: 23129760
HIV; incidence testing; United States; epidemiology

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